CN116783180A - Tricyclic ligands for degradation of IKZF2 or IKZF4 - Google Patents

Tricyclic ligands for degradation of IKZF2 or IKZF4 Download PDF

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CN116783180A
CN116783180A CN202180083722.6A CN202180083722A CN116783180A CN 116783180 A CN116783180 A CN 116783180A CN 202180083722 A CN202180083722 A CN 202180083722A CN 116783180 A CN116783180 A CN 116783180A
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compound
certain embodiments
cancer
pharmaceutically acceptable
disorder
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C·G·纳斯维舒克
J·A·亨德森
M·穆斯塔基姆
A·C·古德
D·普罗亚
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C4 Therapeutics Inc
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems

Abstract

Tricyclic compounds that degrade IKZF2 and/or IKZF4 are provided for use in medical therapy, including abnormal cell proliferation, including cancer, inflammatory disorders, neurodegenerative disorders, or autoimmune disorders.

Description

Tricyclic ligands for degradation of IKZF2 or IKZF4
Cross Reference to Related Applications
The application claims the benefit of U.S. provisional application No. 63/091,875, filed on 10/14/2020, the entire contents of which are incorporated herein by reference for all purposes.
Technical Field
The present application provides tricyclic hydroxycerebroside binders for use in the degradation of IKZF2 (Helios) and/or IKZF4 (Eos) via the ubiquitin proteasome pathway for the treatment of medical conditions mediated by these transcription factors.
Incorporated by reference
The entire content of a text file named "16010-057wo1_sequencelisting_st25.txt" created at 10 months 14 of 2021 and having a size of 3.94KB is incorporated herein by reference.
Background
Protein degradation is a highly regulated and essential process to maintain cellular homeostasis. Selective identification and removal of damaged, misfolded or excess proteins is achieved through the ubiquitin-proteasome pathway (UPP). UPP is central to the regulation of almost all cellular processes including antigen processing, apoptosis, organelle biogenesis, cell cycle, DNA transcription and repair, differentiation and development, immune responses and inflammation, nerve and muscle degeneration, morphogenesis of neural networks, regulation of cell surface receptors, ion channels and secretory pathways, responses to pressure and extracellular modulators, ribosomal biogenesis, and viral infection.
Covalent attachment of multiple ubiquitin molecules to terminal lysine residues by E3 ubiquitin ligase marks the degradation of the protein by proteasome, where the protein is digested into small peptides and eventually into its constituent amino acids as building blocks for new proteins. Defective proteasome degradation is associated with a variety of clinical diseases including alzheimer's disease, parkinson's disease, huntington's disease, muscular dystrophy, cardiovascular disease, cancer, and the like.
The Ikaros (-IKZF ") family is a series of zinc finger protein transcription factors that are important for certain physiological processes, particularly lymphocyte development (see Fan, y. And Lu, d. -The Ikaros family of zinc-finger proteins" Acta Pharmaceutica Sinica B,2016, 6:513-521). Ikaros (-IKZF 1 ") was first discovered in 1992 (see Georgopoulos, K. Et al. -Ikaros, an early lymphoid-specific transcription factor and aputative mediator for T cell commitment" Science,1992, 258:802-812), and four additional homologs have been identified in the following twenty years: helios (-IKZF 2 "), aiolos (-IKZF 3"), eos (-IKZF 4 ") and Pegasus (-IKZF 5") (see John, L.B., and Ward, A.C. the Ikaros gene family: transcriptional regulators of hematopoiesis and immunity "Mol Immunol 2011, 48:1272-1278). Each homologous gene can produce several protein subtypes by alternative splicing, theoretically allowing the production of large amounts of protein complexes by different combinations of the various homologs. Highly conserved among the members of this family is A set of two Cys at the C-terminus 2 His 2 Zinc finger motifs, which mediate protein interactions between individual members of the protein family. Up to 4 zinc finger motifs exist at the N-terminus for recognition of DNA sequences, wherein the number of these N-terminal zinc fingers varies due to alternative splicing. Subtypes without these N-terminal zinc fingers show dominant negative effects on transcriptional activation (see Winandy, S. Et al-A dominant mutation in the Ikaros gene leads to rapid development of leukemia and lymphoma "Cell,1995, 83:289-299).
The distribution of the various members of the Ikaros protein family in vivo is significantly different. Ikaros, helios and Aiolos are mainly present in lymphoid cells and their corresponding progenitors, where Ikaros are also detected in the brain, and Ikaros and Helios are also detected in erythrocytes. EOS and Pegasus are more widely spread and found in skeletal muscles, liver, brain and heart (see Perdomo, J. Et al. — EOS and Pegasus, two members of the Ikaros family of proteins with distinct DNA binding activities: J Biol Chem,2000,275:38347-38354; schmitt, c. Et al. -Aiolos and Ikaros: regulators of lymphocyte development, homeostasis and lymphoproliferation "Apoptosis,2002,7:277-284; yoshida, t. And Georgopoulos, k. -Ikaros fingers on lymphocyte differentiation" Int J hemalol, 2014,100: 220-229).
Regulatory T cells (Tregs) are specialized subpopulations of T cells that suppress immune responses to maintain homeostasis, self-tolerance, and autoimmunity (PMID: 20672742). Tregs can inhibit T cell proliferation and cytokine production. There are many Treg subgroups.
Treg inhibits cd4+ and cd8+ T cells by depleting IL-2, limiting IL-2 expression, and up-regulating CTLA4 to inhibit Antigen Presenting Cells (APCs). Tregs also produce cytokines (IL-10, IL-35 and TGF- β) to inhibit effector T cell activation, and secrete granzyme and/or perforin to destroy effector cells. Furthermore, tregs produce adenosine from ATP in the tumor microenvironment, which can prevent optimized T cell activation.
Tregs antagonize other T cells that attack tumors or cancers. In the cancer setting, excessive Treg activity can prevent the immune system from destroying cancer cells. In autoimmune diseases, too few tregs may allow other autoimmune cells to attack the body's own tissues. The percentage of tregs in the circulation of multiple myeloma patients is significantly higher than in healthy people, and multiple myeloma patients with high tregs survive much shorter.
Treg is FoxP expressing 3 (fork head box P) 3 ) Is a CD4+ T cell subset of FoxP 3 Is a transcription factor, which is the primary regulator of the regulatory pathways that regulate T cell development and function. FoxP (FoxP) 3 Is a marker for natural Treg cells (nTreg) and adaptive/induced T regulatory cells (a/iTreg). Multiple studies have shown FoxP 3 Play an important role in the development of cancer.
IKZF2 and IKZF4 are selectively expressed in Treg cells but not in effector cells or memory cells. FoxP (FoxP) 3 IKZF4/CtBP1 forms an inhibitory complex that inhibits gene expression (IL 2, IFNγ) in tregs and maintains its inhibitory characteristics. Knocking down IKZF4 in tregs abrogates the ability of the cells to suppress immune responses and fulfills part of the effector functions. Mir-17 targets IKZF4 for degradation and its overexpression reduces the inhibitory activity of Treg. Tregs lacking miR-17 exhibit increased inhibition. With mouse FoxP 3 The antisense oligonucleotide treated syngeneic tumor bearing mice significantly attenuated tumor growth. It became clearer that IKZF4 was purified by combining with FoxP 3 Interactions play a key role in controlling many inhibitory functions of tregs.
IKZF2 regulates Treg differentiation through a different mechanism than IKZF 4. Expression of FoxP 3 IKZF2 knockout in Treg via STAT5 (which modulates FoxP 3 ) Promote the loss of inhibitory properties (accompanied by an increase in IL-2) and the expression of T effector cytokines. Similar to the IKZF4 knockout, the IKZF2 knockout fails to prevent autoimmune disease in the inflammatory bowel disease model. IKZF2 is highly expressed in leukemic stem cells and promotes leukemic development. IKZF2 regulates chromatin accessibility and maintains expression of self-renewing transcription factors HOXA9 and MYC in leukemic stem cells. IKZF2 inhibits bone marrow differentiation by inhibiting the accessibility of bone marrow differentiation genes comprising C/EBP motifs.
Unlike IKZF1 and IKZF3, IKZF4 was suggested to be T H 1 gene. It has been shown that IKZF4 expression and T H 1 gene expression at the transcriptional and protein level. Thus, IKZF4 at T H 1 may have opposite effects on the regulation of differentiation and function as IKZF1 and IKZF 3. Furthermore, unlike IKZF1 and IKZF3, IKZF4 can down regulate T H 17 differentiation. Likewise, IKZF4 appears to be associated with T FH The functions of IKZF1 and IKZF3 in cells are reversed.
IKZF2 and IKZF4 have not been and may not be selectively targeted by conventional small molecule inhibitor drugs.
Little research and development has been directed to the identification and use of drugs capable of selectively degrading IKZF2 and/or IKZF 4.
Novartis has an IKZF2/4 protein degrading agent in clinical trials. See Adcock et al, novartis AG, WO 2020/012334; beckwith, et al, novartis AG, WO 2020/012337; visser, et al, novartis AG, WO 2019/038717; and Binazzi, et al, novartis AG, WO 2020/128972.
Dana Farber Cancer Institute also filed in this general field are patent applications: gray, et al, dana-Farber Cancer Institute, WO 2020/006264; and Verano et al Dana Farber Cancer Institute, WO 2020/117759, and WO 2021/087093. IKZF2 degrading agents have also been proposed by Bristol-Myers Squibb company, for example WO2021/101919 and WO2021/194914.
Ionis Pharmaceuticals and Astra Zeneca have reported targeting FoxP 3 And inhibits high affinity oligonucleotides (AZD 8701) that regulate T cell immunosuppressive function and produce antitumor effects in syngeneic mice (AACR Annual Meeting Abst5561;2018, month 4).
PCT/US2019/24094 and PCT/US2020/02678 filed by C4 Therapeutics, inc. disclose a hydroxy cerebroside ester binding agent (IKZF 1/3) for use in degrading Ikaros.
WO2021/127586 filed by Calico Life Sciences LLC and AbbVie Inc describes PTPN1 and PTPN2 ligands covalently bound to various hydroxycerebroside ligands.
Despite these efforts, there remains a need for compounds that catalyze the selective degradation of zinc finger proteins such as IKZF2 and IKZF4 for medical treatment, including for the treatment of conditions involving abnormal cell proliferation, including tumors and cancers.
Summary of The Invention
Certain tricycloglutarimide compounds have been found to degrade IKZF2 and/or IKZF4. Furthermore, in certain embodiments, these tricyclic compounds selectively degrade IKZF2 and/or IKZF4 over IKZF1 or IKZF 3. Thus, there is provided novel tricyclic compounds that may be administered to a host, typically a human, in an effective amount to treat medical conditions including, for example, abnormal cell proliferation including cancer, inflammatory conditions, neurodegenerative conditions, and autoimmune conditions, responsive to agents that selectively degrade IKZF2 and/or IKZF4. The invention includes the IKZF2 and/or IKZF4 degradation agents and pharmaceutically acceptable salts thereof, and uses and preparations thereof.
In certain embodiments, the tricyclic compounds of the invention are at least about 1.5, 2, 3, 5, or even 10-fold selective for the in vitro degradation of IKZF2 and/or IKZF4 over IKZF1 and/or IKZF3 in a standard HiBiT bioluminescence assay.
In certain embodiments, by selectively degrading IKZF2 and/or IKZF4, the tricycloglutarimides described herein, or pharmaceutically acceptable salts thereof, are useful in treating diseases that are in an immunosuppressive environment due to the presence of Treg cells and/or other related cytokines and mediators that reduce the normal immune response of the host to the disease. In one non-limiting embodiment, the biomarker FoxP of a host biopsy can be tested 3 Or up-regulation of IL-10, IL-35 or TGF-beta to determine optimal therapy.
The selected compounds disclosed herein, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof, are useful in treating disorders mediated by IKZF2 or IKZF4, for example solid tumors such as lung cancer, including small cell lung cancer or non-small cell lung cancer (e.g., those refractory to PD-1 or PD-L1), melanoma (e.g., those refractory to PD-1 or PD-L1), breast cancer (including triple negative breast cancer), or hematopoietic malignancies such as multiple myeloma, leukemia, acute myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, or a combination thereof It is targeted for indications. In certain embodiments, the cancer is a cancer with increased FoxP 3 CLL of cd4+ cells. Jurkat cells (T-ALL) are known to express IKZF2 and IKZF4, and thus these compounds are useful in the treatment of T-ALL. Other examples of cancers mediated by IKZF2 or IKZF4 include T cell leukemia, T cell lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, myeloid leukemia, nasopharyngeal carcinoma, microsatellite stabilized colorectal carcinoma, thymoma and carcinoid.
In certain embodiments, the selective degradation agent that administers IKZF2 and/or IKZF4 to a host in need thereof is combined with another active agent (e.g., a checkpoint inhibitor, CAR-T therapy, a targeting antibody, an antibody drug conjugate, or other standard-of-care therapy for the treated cancer or abnormal cell proliferation). In certain embodiments, the patient has cancer that progresses on immune checkpoint inhibitor therapy, has a high tumor burden, is over about 60 or 65 years old, or has an increased number of Treg markers. When used in combination with another compound or biologic for the treatment of immunosuppression, it can result in activation of cd4+ T cells, cd8+ T cells, B cells, NK cells, macrophages or dendritic cells and enhanced effector function.
The present invention provides compounds of formula I:
or a pharmaceutically acceptable salt, N-oxide, isotopic derivative, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition;
R 1 is that
Q 1 Is CH or N;
x is selected from the group consisting of bond, alkyl, aliphatic, heterocyclic (which may be bonded through C and/or N in the ring), aryl, heteroaryl, bicyclic, -NR 27 -、-NR 10 -、-CR 40 R 41 -、-O-、-C(O)-、-C(NR 27 )-、-C(S)-、-S(O)-、-S(O) 2 -and-S-; where the valences permit formation of stable compounds, each of which is optionally substituted with 1, 2, 3 or 4 groups independently selected from non-hydrogen R 40 Is substituted by a substituent of (a);
R 15 、R 16 and R is 17 Independently at each occurrence selected from the group consisting of bond, alkyl, -C (O) -, -C (O) O-, -OC (O) -, -SO 2 -、-S(O)-、-C(S)-、-C(O)NR 27 -、-NR 27 C(O)-、-O-、-S-、-NR 27 -、-NR 10 -、-C(R 40 R 41 ) -, bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, cycloalkyl, heteroaliphatic, and heteroaryl; where the valences permit to form stable compounds, each of which is optionally substituted with 1, 2, 3 or 4 groups of compounds independently selected from R 40 Is substituted by a substituent of (a); and wherein R is 15 、R 16 And R is 17 Not more than two of which are selected as keys;
R 18 selected from hydrogen, halogen, cyano, -C (O) R 27 、-C(O)OR 27 Alkyl, -C (O) NR 10 R 27 、-NR 27 C(O)R 27 、–NR 10 R 27 、-OR 27 、-SR 27 Alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, and heteroaryl; where the valences permit to form stable compounds, each of which is optionally substituted with 1, 2, 3 or 4 groups of compounds independently selected from R 40 Is substituted by a substituent of (a); and therein X, R 15 、R 16 、R 17 And R is 18 As known to those skilled in the art, in combinations selected to provide R that is stable under the environmental conditions of use and the desired shelf life (e.g., at least about 2, 3, 4, 5, or 6 months or more) 1 A portion; typically, select X, R 15 、R 16 、R 17 And R is 18 So that no more than 1, 2 or 3 heteroatoms may be sequentially attached;
R 27 independently at each occurrence, selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, cycloalkyl, aliphatic, and heteroaliphatic;
R 40 independently at each occurrence selected from hydrogen, aliphatic, heteroaliphatic, cyano, nitro, alkyl, halo (including in particular F, cl, br), haloalkyl, -OR 10 、-SR 10 、-S(O)R 12 、-SO 2 R 12 and-NR 10 R 11 ；
R 41 Is aliphatic, aryl, heteroaryl, or hydrogen;
a is selected from:
n is 0, 1 or 2;
X 3 is NR 10 、NR 6’ O or S;
q is CR 7 Or N;
R 3 is hydrogen, alkyl, halogen or haloalkyl;
or R is 3 And R is 6 To form a 1 or 2 carbon linkage;
or R is 3 And R is 4 To form a 1, 2, 3 or 4 carbon linkage;
or R is 3 And R is equal to 3 Adjacent R 4 The groups combine to form a double bond.
R 4 And R is 5 Independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 、-SR 10 、-S(O)R 12 、-SO 2 R 12 and-NR 10 R 11 ；
R 6 And R is 7 Independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 、-SR 10 、-S(O)R 12 、-SO 2 R 12 and-NR 10 R 11 ；
R 6 ' is hydrogen, alkyl or haloalkyl;
or R is 3 And R is 6 ' bindingTo form a 1 or 2 carbon linkage.
Each R 10 And R is 11 Independently selected from hydrogen, aliphatic, alkyl, haloalkyl, heterocycle, aryl, heteroaryl, -C (O) R 12 、-S(O)R 12 and-SO 2 R 12 ；
Each R 12 Independently selected from hydrogen, alkyl, haloalkyl, heterocycle, aryl, heteroaryl, -NR 13 R 14 And OR 13 The method comprises the steps of carrying out a first treatment on the surface of the And
r in each case 13 And R is 14 Independently selected from hydrogen, alkyl and haloalkyl.
Each combination of variables, substituents, embodiments and compounds resulting from these combinations is considered specific and individually disclosed, as such description is for convenience of illustration only and is not intended to describe only the genus or even subgenera of compounds, but rather to provide each of the following that is stable to the compound under the environmental conditions of use and shelf life required (e.g., at least about 2, 3, 4, 5 or 6 months or more), as known to those skilled in the art.
In certain embodiments, the compounds described herein bind to a hydroxycerebroside, increasing the interaction between the hydroxycerebroside and IKZF2 or IKZF4 and leading to subsequent ubiquitination and degradation of the protein in the proteasome.
Thus, in some embodiments, based on this discovery, compounds and methods are provided for treating patients suffering from a disorder mediated by IKZF2 or IKZF4, which in certain embodiments is a lymphoid disorder. In certain embodiments, the disorder is leukemia. In certain embodiments, the disorder is lymphocytic leukemia. In certain embodiments, the disorder is lymphoblastic leukemia. In some embodiments, the disorder is a hematological malignancy, such as multiple myeloma, myelodysplastic syndrome, such as 5 q-syndrome, acute lymphoblastic leukemia, hodgkin's lymphoma, non-hodgkin's lymphoma, myeloid leukemia, acute myeloid leukemia, chronic myeloid leukemia, or chronic lymphocytic leukemia. In another embodiment, selected compounds of the invention are administered to achieve immunomodulation and reduced angiogenesis.
In other embodiments, compounds and methods are presented for treating conditions including, but not limited to, benign growth, neoplasms, tumors, cancers, abnormal cell proliferation, immune disorders, inflammatory disorders, graft versus host rejection, viral infections, bacterial infections, amyloid-based proteinopathies, or fibrotic disorders. In addition, other conditions that may be treated with an effective amount of the compounds described herein are described below.
In certain embodiments, any of the compounds described herein have at least one desired atomic substitution in an amount that is about the natural abundance (i.e., enrichment) of the isotope.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
Accordingly, the present invention includes at least the following features:
(a) A compound of formula I as described herein or a pharmaceutically acceptable salt, isotopic derivative (including deuterated derivatives) or prodrug thereof;
(b) A compound of formula I as described herein or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof for use in the treatment of a disorder mediated by IKZF2 or IKZF 4;
(c) A method of treating a patient (typically a human) in need thereof, comprising administering an effective amount of a compound of formula I as described herein or a pharmaceutically acceptable salt thereof, wherein the patient has a disorder described herein, e.g., a disorder mediated by IKZF2 or IKZF 4;
(d) A method of treating a patient (typically a human) in need thereof, comprising administering an effective amount of a compound of formula I as described herein or a pharmaceutically acceptable salt thereof, wherein the patient has a hematological malignancy, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, hodgkin lymphoma or non-hodgkin lymphoma;
(e) A method of treating a patient (typically a human) in need thereof, comprising administering an effective amount of a compound of formula I as described herein or a pharmaceutically acceptable salt thereof, wherein the patient has a solid malignancy, such as non-small cell lung cancer, breast cancer, melanoma, prostate cancer, colon cancer, pancreatic cancer; or cancer that generally exhibits an immunosuppressive environment;
(f) A method of treating a patient (typically a human) in need thereof, comprising administering an effective amount of a compound of formula I as described herein or a pharmaceutically acceptable salt thereof, wherein the patient has a solid malignancy, such as non-small cell lung cancer, breast cancer, melanoma, prostate cancer, colon cancer, pancreatic cancer; or a cancer that normally exhibits an immunosuppressive environment, and wherein the patient is also administered an anti-PD-1 or anti-PD-L1 agent;
(g) Use of an effective amount of a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, in the treatment of a patient (typically a human) suffering from any of the disorders described herein, including those mediated by IKZF2 or IKZF 4;
(h) Use of a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for the manufacture of a medicament for the treatment of a medical condition susceptible to said compound, as further described herein;
(i) A method of preparing a medicament for treating a condition described herein in a host, characterized in that a compound of formula I is used in the preparation;
(j) A compound of formula I as described herein or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof for use in treating cancer (including any cancer described herein) in a host;
(k) Use of a compound of formula I as described herein, or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for the manufacture of a medicament for the treatment of cancer (including any cancer described herein);
(l) A method of preparing a medicament for the treatment of cancer (including any of the cancers described herein) in a host, characterized in that a compound of formula I is used in the preparation;
(m) a compound of formula I as described herein or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for use in treating a tumor (including any tumor described herein) in a host;
(n) use of a compound of formula I as described herein or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, in the manufacture of a medicament for the treatment of a tumor (including any of the tumors described herein);
(o) a method of preparing a medicament for the treatment of a tumor (including any of the tumors described herein) in a host, characterized in that a compound of formula I is used in the preparation;
(p) a compound of formula I as described herein or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for use in the treatment of an immune, autoimmune, inflammatory, neurodegenerative or fibrotic disorder in a host;
(q) use of a compound of formula I as described herein or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, in the manufacture of a medicament for the treatment of an immune, autoimmune, inflammatory, neurodegenerative or fibrotic disorder;
(r) a method of preparing a medicament for treating an immune, autoimmune, inflammatory, neurodegenerative or fibrotic disorder in a host, characterized in that a compound of formula I is used in the preparation;
(s) a compound of formula I as described herein or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for use in the treatment of hematological malignancies, such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, hodgkin's lymphoma or non-hodgkin's lymphoma;
(t) a compound of formula I as described herein or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for use in the treatment of a solid malignancy, such as non-small cell lung cancer, breast cancer, melanoma, prostate cancer, colon cancer, pancreatic cancer; or cancer that generally exhibits an immunosuppressive environment;
(u) use of a compound of formula I as described herein or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, for the manufacture of a medicament for the treatment of hematological malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, hodgkin's lymphoma or non-hodgkin's lymphoma;
(v) A method of preparing a medicament for the treatment of hematological malignancies such as multiple myeloma, leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, hodgkin's lymphoma or non-hodgkin's lymphoma;
(w) a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I as described herein or a pharmaceutically acceptable salt, isotopic derivative or prodrug thereof, and a pharmaceutically acceptable carrier or diluent;
(x) A compound as described herein, as a mixture of enantiomers or diastereomers (e.g., related), including racemates;
(y) a compound as described herein in enantiomerically or diastereomerically (e.g., related) enriched form, including isolated enantiomers or diastereomers (i.e., greater than 85, 90, 95, 97, or 99% pure); and
(z) a process for preparing a therapeutic product comprising an effective amount of a compound of formula I as described herein.
Drawings
FIG. 1 is a schematic diagram showing a 3- (5-bromo-2-oxo-benzo [ cd ] movable with an intermediate]Indol-1 (2H) -yl) piperidine-2, 6-dione is used together to add a series of R 1 Non-limiting examples of synthetic schemes for the synthesis of groups.
FIG. 2 is a schematic diagram showing a compound which can be combined with the intermediate 1- (2, 6-dioxopiperidin-3-yl) -2-oxo-1, 2-dihydrobenzo [ cd ]]Indole-5-carbaldehyde derivatives are used together to functionalize a range of R 1 Non-limiting examples of synthetic schemes for the synthesis of groups.
FIG. 3 is a representative formula of an IKZF2/4 degrading compound of the invention.
Detailed Description
Definition of the definition
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In the specification, the singular forms also include the plural unless the context clearly dictates otherwise. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. The references cited herein are not to be considered prior art to the claimed application. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
In certain embodiments of each of the compounds described herein, the compound may be in the form of a racemate, an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of diastereomers, a tautomer, an N-oxide, or an isomer, such as a rotamer, unless the context clearly dictates otherwise, as if each were explicitly described.
The terms a/an do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term-or "refers to-and/or. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are inclusive of the range and independently combinable. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of example or exemplary language (e.g., -as ") is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed.
The invention includes compounds described herein that have at least one desired isotopic substitution of an atom in an amount higher than the natural abundance of that isotope, i.e., enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., atoms having the same number of protons but different numbers of neutrons. If isotopic substitution is used, the typical substitution is at least one deuterium substitution for hydrogen.
More generally, examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, respectively, such as 2 H、 3 H、 11 C、 13 C、 14 C、 15 N、 17 O、 18 O、 18 F、 35 S and 36 cl. In one non-limiting embodiment, isotopically-labeled compounds can be used in metabolic studies (e.g., with 14 C) Reaction kinetics studies (using, for example 2 H or 3 H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT), including drug or substrate tissue distribution assays, or for radiation therapy of patients. In addition, any hydrogen atom present in the compounds of the invention may be replaced 18 F atom substitution, which may be particularly desirable for PET and SPECT studies. Isotopically-labeled compounds of the present invention and prodrugs thereof can generally be prepared by the procedures disclosed in the embodiments or examples and by the preparation methods described below by substituting a readily available isotopically-labeled reagent for a non-isotopically-labeled reagent.
By way of general example and not limitation, isotopes of hydrogen, such as deuterium 2 H) And tritium% 3 H) Can be used anywhere in the structure where the desired result is achieved. Alternatively or additionally isotopes of carbon may be used, for example 13 C and C 14 C。
Isotopic substitution, such as deuterium substitution, may be partial or complete. Partial deuterium substitution refers to substitution of at least one hydrogen with deuterium. In certain embodiments, an isotope is enriched in 90, 95, or 99% or more at any target site with the isotope. In one non-limiting embodiment, deuterium is enriched at the desired position by 90, 95 or 99%.
In one non-limiting embodiment, substitution of a deuterium atom for a hydrogen atom may be provided in any of the compounds described herein. For example, when any group is or contains (e.g., by substitution) methyl, ethyl, or methoxy, the alkyl residue may be deuterated (in non-limiting embodiments, CDH 2 、CD 2 H、CD 3 、CH 2 CD 3 、CD 2 CD 3 、CHDCH 2 D、CH 2 CD 3 、CHDCHD 2 、OCDH 2 、OCD 2 H or OCD 3 Etc.). In certain other embodiments, when two substituents combine to form a ring, the unsubstituted carbon may be deuterated. In certain embodiments, at least one deuterium is located on an atom having a bond that breaks during metabolism in the compound or is one, two or three atoms away from the metabolic bond (e.g., which may be referred to as α, β or γ, or primary, secondary or tertiary isotope effects).
The compounds of the present invention may form solvates with solvents, including water. Thus, in one non-limiting embodiment, the invention includes solvated forms of the compounds described herein. The term "solvate" refers to a molecular complex of a compound of the invention (including salts thereof) with one or more solvent molecules. Non-limiting examples of solvents are water, ethanol, isopropanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term "hydrate" refers to a molecular complex comprising a compound of the invention and water. Pharmaceutically acceptable solvates according to the invention include those wherein the solvent may be isotopically substituted (e.g., D 2 O、d 6 Acetone, d 6 -DMSO). Solvates may be in liquid or solid form.
Dashes (— ") that are not between two letters or symbols are used to indicate the point of attachment of the substituent. For example, - (c=o) NH 2 Carbon linkage through the ketone (c=o) group.
Alkyl group"is a branched or straight chain saturated aliphatic hydrocarbon group. In one non-limiting embodiment, the alkyl group contains from 1 to about 12 carbon atoms, more typically from 1 to about 6 carbon atoms or from 1 to about 4 carbon atoms. In one non-limiting embodiment, the alkyl group contains from 1 to about 8 carbon atoms. In certain embodiments, alkyl is C 1 -C 2 、C 1 -C 3 、C 1 -C 4 、C 1 -C 5 Or C 1 -C 6 . As used herein, a particular range indicates an alkyl group having each member of the range described as an independent substance. For example, the term C as used herein 1 -C 6 Alkyl indicates a straight or branched alkyl group having 1, 2,3, 4, 5 or 6 carbon atoms and is intended to mean that each of these is described as an independent substance. For example, the term C as used herein 1 -C 4 Alkyl indicates a straight or branched alkyl group having 1, 2,3 or 4 carbon atoms and is intended to mean that each of these is described as an independent substance. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2-dimethylbutane and 2, 3-dimethylbutane.
Alkenyl "is a straight or branched aliphatic hydrocarbon group having one or more carbon-carbon double bonds, which may be present at stable points along the chain. As used herein, a particular range indicates alkenyl groups having each member of the range described as independent species, as described above for the alkyl portion. In one non-limiting embodiment, alkenyl groups contain 2 to about 12 carbon atoms, more typically 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, alkenyl is C 2 、C 2 -C 3 、C 2 -C 4 、C 2 -C 5 Or C 2 -C 6 . Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, allyl, propenyl, butenyl, and 4-methylbutenyl. The term-alkeneThe radicals "also embody the-cis" and-trans "alkenyl geometries, or alternatively, the-E" and-Z "alkenyl geometries. The term-alkenyl "also includes cycloalkyl or carbocyclic groups having at least one point of unsaturation.
Alkynyl "is a branched or straight chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds, which may occur at any stable point along the chain. As used herein, a particular range indicates alkynyl groups having each member of the range described as independent of the species as described above for the alkyl moiety. In one non-limiting embodiment, alkynyl groups contain 2 to about 12 carbon atoms, more typically 2 to about 6 carbon atoms or 2 to about 4 carbon atoms. In certain embodiments, alkynyl is C 2 、C 2 -C 3 、C 2 -C 4 、C 2 -C 5 Or C 2 -C 6 . Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
The halo "and-halogen" are independently fluorine, chlorine, bromine or iodine.
Haloalkyl "is a branched or straight-chain alkyl group substituted with 1 or more of the above halogen atoms, up to the maximum permissible number of halogen atoms. Examples of haloalkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Perhaloalkyl "means an alkyl group in which all hydrogen atoms are replaced by halogen atoms. Examples include, but are not limited to, trifluoromethyl and pentafluoroethyl.
As used herein, an "aryl" refers to an aromatic ring system (-C) 6–14 Aryl ") in which a mono-or polycyclic (e.g., bi-or tri-cyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and zero heteroatoms is provided (e.g., sharing 6, 10 or 14 pi electrons in a cyclic array) Son) groups. In some embodiments, the aryl group has 6 ring carbon atoms (-C 6 Aryl "; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms (-C 10 Aryl "; for example, naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms (-C 14 Aryl "; for example, anthracyl). Aryl "also includes ring systems in which an aryl ring as defined above is fused with one or more cycloalkyl or heterocyclic groups, wherein the linking group or point of attachment is located on the aryl ring, and in which case the number of carbon atoms still designates the number of carbon atoms in the aryl ring system. The one or more fused cycloalkyl or heterocyclic groups may be 4-to 7-membered saturated or partially unsaturated cycloalkyl or heterocyclic groups.
Arylalkyl means an alkyl group as defined herein substituted with an aryl group as defined herein or an aryl group as defined herein substituted with an alkyl group as defined herein.
The term-heterocycle "means saturated and partially saturated heteroatom-containing ring groups in which 1,2,3 or 4 heteroatoms independently selected from nitrogen, sulfur, boron, silicone and oxygen are present. The heterocycle may comprise a monocyclic 3-10 membered ring and a 5-16 membered bicyclic ring system (which may include bridged, fused and spiro-fused bicyclic ring systems). It does not include a catalyst containing-O-; -O-S-or-S-moiety. Examples of the saturated heterocyclic group include saturated 3-to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms [ e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl ]; a saturated 3-to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [ e.g., morpholinyl ]; saturated 3-to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [ e.g., thiazolidine group ]. Examples of partially saturated heterocyclic groups include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocyclic groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2, 3-dihydro-benzo [ l,4] dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, isochromanyl, chromanyl, 1, 2-dihydroquinolinyl, 1,2,3, 4-tetrahydro-isoquinolinyl, 1,2,3, 4-tetrahydro-quinolinyl, 2,3, 4a,9 a-hexahydro-lH-3-aza-fluorenyl, 5,6, 7-dihydro-l, 2, 4-triazolo [3,4-a ] isoquinolinyl, 3, 4-dihydro-2H-benzo [ l,4] oxazinyl, benzo [ l,4] dioxanyl, 2, 3-dihydro-l '-dihydro-H' -benzo [ l, d ] thiazolyl, and dihydrothiazolyl.
Heterocyclic "also includes groups in which the heterocyclic group is fused/condensed with an aryl or carbocyclic group, wherein the point of attachment is a heterocycle. Heterocyclic rings also include those wherein the heterocyclic group is substituted with an oxo group (i.e) A substituted group. For example, a partially unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms, such as indoline or isoindoline; a partially unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms; a partially unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms; and saturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms.
The term "heterocycle" also includes a bicyclic heterocycle. The term-bicyclic heterocycle "means a heterocycle as defined herein wherein there is one bridging, fused or spiro moiety of the heterocycle. The bridged, fused or spiro moiety of the heterocycle may be carbocyclic, heterocyclic or aryl, provided that a stable molecule is obtained. Unless the context precludes, the term "heterocycle" includes bicyclic heterocycles. Bicyclic heterocycles include groups in which the fused heterocycle is substituted with an oxo group. Non-limiting examples of bicyclic heterocycles include:
the term-heteroaryl "means a stable aromatic ring system containing 1,2,3 or 4 heteroatoms independently selected from O, N and S, wherein the ring nitrogen and sulfur atoms are optionally oxidized and the nitrogen atom is optionally quaternized. Examples include, but are not limited to, unsaturated 5-to 6-membered heteromonocyclic groups containing 1-4 nitrogen atoms, such as pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [ e.g., 4H-l,2, 4-triazolyl, 1H-1,2, 3-triazolyl, 2H-l,2, 3-triazolyl ]; unsaturated 5-to 6-membered heteromonocyclic group containing an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.; unsaturated 5-to 6-membered heteromonocyclic group containing sulfur atom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5-to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [ e.g., 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 5-oxadiazolyl ]; unsaturated 5-to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [ e.g., 1,2, 4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl ]. In certain embodiments, the —heteroaryl "is an 8, 9, or 10 membered bicyclic ring system. 8. Examples of 9-or 10-membered bicyclic heteroaryl groups include benzofuranyl, benzothienyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, quinolinyl, isoquinolinyl, benzofuranyl, indolyl, indazolyl and benzotriazole groups.
Heteroarylalkyl "refers to an alkyl group as defined herein substituted with a heteroaryl group as defined herein or a heteroaryl group as defined herein substituted with an alkyl group as defined herein.
As used herein, carbocycle ", -carbocycle" or-cycloalkyl "includes those containing all carbon ring atoms and 3 to 14 ring carbon atoms (-C) 3–14 Cycloalkyl ") and saturated or partially unsaturated (i.e., non-aromatic) groups of zero heteroatoms in the non-aromatic ring system. In some embodiments, cycloalkyl groups have 3 to 10 ring carbon atoms (-C 3–10 Cycloalkyl "). In some embodiments, cycloalkyl groups have 3 to 9 ring carbon atoms (-C 3–9 Cycloalkyl "). In some embodiments, cycloalkyl groups have 3 to 8 ring carbon atoms (-C 3–8 Cycloalkyl "). In some embodiments, cycloalkyl groups have 3 to 7 ring carbon atoms (-C 3–7 Cycloalkyl "). In some embodiments, cycloalkyl has 3 to 6Ring carbon atom (-C) 3–6 Cycloalkyl "). In some embodiments, cycloalkyl groups have 4 to 6 ring carbon atoms (-C 4-6 Cycloalkyl "). In some embodiments, cycloalkyl groups have 5 to 6 ring carbon atoms (-C 5-6 Cycloalkyl "). In some embodiments, cycloalkyl groups have 5 to 10 ring carbon atoms (-C 5-10 Cycloalkyl "). Exemplary C 3-6 Cycloalkyl groups include, but are not limited to, cyclopropyl (C) 3 ) Cyclopropenyl (C) 3 ) Cyclobutyl (C) 4 ) Cyclobutenyl (C) 4 ) Cyclopentyl (C) 5 ) Cyclopentenyl (C) 5 ) Cyclohexyl (C) 6 ) Cyclohexenyl (C) 6 ) Cyclohexadienyl (C) 6 ) Etc. Exemplary C 3-8 Cycloalkyl groups include, but are not limited to, C described above 3-6 Cycloalkyl and cycloheptyl (C) 7 ) Cycloheptenyl (C) 7 ) Cycloheptadienyl (C) 7 ) Cycloheptatrienyl (C) 7 ) Cyclooctyl (C) 8 ) Cyclooctenyl (C) 8 ) Etc. Exemplary C 3-10 Cycloalkyl groups include, but are not limited to, C described above 3-8 Cycloalkyl and cyclononyl (C) 9 ) Cyclononenyl (C) 9 ) Cyclodecyl (C) 10 ) Cyclodecenyl (C) 10 ) Etc. As shown in the foregoing examples, in certain embodiments, the cycloalkyl groups may be saturated or may contain one or more carbon-carbon double bonds. The term-cycloalkyl "also includes ring systems wherein the cycloalkyl ring as defined above is fused to a heterocyclic, aryl or heteroaryl ring, wherein the point of attachment is on the cycloalkyl ring, and in which case the carbon number continues to represent the number of carbons in the carbocyclic ring system. The term-cycloalkyl "also includes ring systems wherein the cycloalkyl ring as defined above has a spiro heterocycle, aryl ring or heteroaryl ring, wherein the point of attachment is on the cycloalkyl ring, and in which case the number of carbon atoms continues to represent the number of carbon atoms in the carbocyclic ring system. The term-cycloalkyl "also includes bicyclic or polycyclic fused, bridged or spiro ring systems containing 5 to 14 carbon atoms and zero heteroatoms in the non-aromatic ring. Representative examples of cycloalkyl groups include, but are not limited to
The term-bicyclic "refers to a ring system in which two rings are fused together and each ring is independently selected from carbocycles, heterocycles, aryl and heteroaryl. Non-limiting examples of bicyclic rings include:
when the term-bicyclic "is at a divalent residue such as R 15 、R 16 Or R is 17 When used in the context of (a), the connection points may be on different rings or on the same ring. In certain embodiments, both attachment points are on the same ring. In certain embodiments, both attachment points are on different rings. Non-limiting examples of bicyclic rings include:
dosage form "refers to the unit of administration of the active agent. Examples of dosage forms include tablets, capsules, injections, suspensions, liquids, emulsions, implants, granules, spheres, creams, ointments, suppositories, inhalable dosage forms, transdermal dosage forms, oral, sublingual, topical, gel, mucosal, and the like. Dosage form "may also comprise implants, such as optical implants.
As used herein, endogenous refers to any material from or produced within an organism, cell, tissue or system.
As used herein, the term-exogenous "refers to any material introduced from or produced outside an organism, cell, tissue or system.
As used herein, the term "modulate" refers to mediating a detectable increase or decrease in the level of a response in an individual compared to the level of a response in an individual in the absence of a treatment or compound, and/or comparing the level of a response in an otherwise identical but untreated individual. The term includes disruption and/or influence of the natural signal or response, thereby mediating a beneficial therapeutic response in an individual, preferably a human.
Parenteral "administration of a compound includes, for example, subcutaneous (s.c.), intravenous (i.v.), intramuscular (i.m.), or intrasternal injection, or infusion techniques.
As used herein, a pharmaceutical composition "is a composition comprising at least one active agent, such as a selected active compound described herein, and at least one other substance, such as a carrier. A pharmaceutical combination "is a combination of at least two active agents, which may be combined in a single dosage form or provided together in separate dosage forms, together with instructions for the use of the active agents together for the treatment of any of the diseases described herein.
As used herein, a pharmaceutically acceptable salt "is a derivative of the disclosed compounds wherein the parent compound is modified by preparing inorganic and organic, acid or base addition salts thereof, which are biologically acceptable without toxicity. Salts of the compounds of the present invention may be synthesized from the parent compound containing a basic or acidic moiety by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., na, ca, mg or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are generally carried out in water or organic solvents or in a mixture of both. Typically, where feasible, a typical nonaqueous medium is diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. Salts of the compounds of the invention also include compounds and solvates of salts of the compounds.
Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues such as amines; alkali metal salts or organic salts of acidic residues such as carboxylic acids; and so on. Pharmaceutically acceptable salts include conventional non-toxic salts and quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; and acids selected from the group consisting of organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-benzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC- (CH 2) n-COOH, where n is 0-4, and the like, or different acids that produce the same counter ion are used. A list of other suitable salts can be found, for example, in Remington's Pharmaceutical Sciences, 17 th edition, mack Publishing Company, easton, pa., page 1418 (1985).
The term "carrier" refers to a diluent, excipient, or carrier with which the active agent is used or delivered.
Pharmaceutically acceptable excipients "refer to excipients that can be used to prepare a pharmaceutical composition/combination that is generally safe and biologically or otherwise unsuitable for administration to a host, typically a human. In certain embodiments, excipients useful for veterinary purposes are used.
A patient "or-host" or-individual "is a human or non-human animal in need of treatment for any of the conditions specifically described herein. Typically, the host is a human. The host "may alternatively refer to, for example, mammals, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc.
A therapeutically effective amount "of a pharmaceutical composition/combination of the present invention refers to an amount that is effective when administered to a host to provide a therapeutic benefit such as an improvement in symptoms or a reduction or alleviation of the disease itself.
In certain embodiments, a prodrug "is a form of the parent molecule that is metabolized or chemically converted to the parent molecule in vivo (e.g., in a mammal or human). Non-limiting examples of prodrugs include esters, amides (e.g., primary or secondary amines), carbonates, carbamates, phosphates, ketals, imines, oxazolidines, and thiazolidines. Prodrugs can be designed to release the parent molecule upon a pH change (e.g., in the stomach or intestine) or under the action of an enzyme (e.g., esterase or amidase).
In certain embodiments, stable means less than 10%, 5%, 3% or 1% of the compound degrades under ambient conditions and a shelf life of at least 3, 4, 5 or 6 months. In certain embodiments, the compounds stored under ambient conditions are stored at about room temperature and exposed to air and a relative humidity of less than about 40%, 50%, 60%, or 70%. In certain embodiments, the compounds stored under ambient conditions are stored under an inert gas (e.g., argon or nitrogen) at about room temperature. Typically, a moiety as described herein does not have more than one or two heteroatoms directly bonded to each other unless the moiety is heteroaromatic.
Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description of the range format is merely for convenience and is not to be construed as limiting the scope of the invention. It should be understood that the description of a range has specifically disclosed all possible sub-ranges and individual values within that range. For example, descriptions of ranges such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6, etc., as well as individual numbers within the range such as 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.
II Compounds of the invention
Embodiments of "alkyl
In certain embodiments, the —alkyl "is C 1 -C 10 Alkyl, C 1 -C 9 Alkyl, C 1 -C 8 Alkyl, C 1 -C 7 Alkyl, C 1 -C 6 Alkyl, C 1 -C 5 Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl or C 1 -C 2 An alkyl group.
In certain embodiments, the —alkyl "has one carbon.
In certain embodiments, an alkyl group "has two carbons.
In certain embodiments, an alkyl group "has three carbons.
In certain embodiments, the —alkyl "has four carbons.
In certain embodiments, the —alkyl "has five carbons.
In some embodiments, the —alkyl "has six carbons.
Non-limiting examples of alkyl groups include: methyl, ethyl, propyl, butyl, pentyl and hexyl.
Other non-limiting examples of alkyl groups include: isopropyl, isobutyl, isopentyl, and isohexyl.
Other non-limiting examples of alkyl groups include: sec-butyl, sec-pentyl and sec-hexyl.
Other non-limiting examples of alkyl groups include: tertiary butyl, tertiary amyl, and tertiary hexyl.
Other non-limiting examples of alkyl groups include: neopentyl, 3-pentyl and active pentyl.
Embodiments of "haloalkyl
In certain embodiments, the —haloalkyl "is C 1 -C 10 Haloalkyl, C 1 -C 9 Haloalkyl, C 1 -C 8 Haloalkyl, C 1 -C 7 Haloalkyl, C 1 -C 6 Haloalkyl, C 1 -C 5 Haloalkyl, C 1 -C 4 Haloalkyl, C 1 -C 3 Haloalkyl and C 1 -C 2 A haloalkyl group.
In certain embodiments, the-haloalkyl "has one carbon.
In certain embodiments, the-haloalkyl "has one carbon and one halogen.
In certain embodiments, the-haloalkyl "has one carbon and two halogens.
In certain embodiments, the-haloalkyl "has one carbon and three halogens.
In certain embodiments, the-haloalkyl "has two carbons.
In certain embodiments, the-haloalkyl "has three carbons.
In certain embodiments, the-haloalkyl "has four carbons.
In certain embodiments, the-haloalkyl "has five carbons.
In certain embodiments, the-haloalkyl "has six carbons.
Non-limiting examples of haloalkyl groups include:
other non-limiting examples of haloalkyl groups include:
other non-limiting examples of haloalkyl groups include:
other non-limiting examples of haloalkyl groups include:
embodiments of "aryl
In certain embodiments, an —aryl "is a 6 carbon aromatic group (phenyl).
In certain embodiments, an —aryl "is a 10 carbon aromatic group (naphthyl).
In certain embodiments, an —aryl "is a 6 carbon aromatic group fused to a heterocycle, wherein the point of attachment is an aromatic ring. Non-limiting examples of aryl groups include indoline, tetrahydroquinoline, tetrahydroisoquinoline and dihydrobenzofuran, wherein the point of attachment of each group is on an aromatic ring.
For example, the number of the cells to be processed,is an-aryl "group.
However, the process is not limited to the above-described process,is a heterocyclic "group.
In certain embodiments, an —aryl "is a 6 carbon aromatic group fused to a cycloalkyl, wherein the point of attachment is an aromatic ring. Non-limiting examples of aryl groups include indanes and tetrahydronaphthalenes, wherein the point of attachment of each group is on an aromatic ring.
For example, the number of the cells to be processed,is an-aryl "group.
However, the process is not limited to the above-described process,is a cycloalkyl "group.
Embodiments of "heteroaryl
In certain embodiments, a-heteroaryl "is a 5-membered aromatic group containing 1, 2, 3, or 4 nitrogen atoms.
Non-limiting examples of 5-membered-heteroaryl "include pyrrole, furan, thiophene, pyrazole, imidazole, triazole, tetrazole, isoxazole, oxazole, oxadiazole, oxatriazole, isothiazole, thiazole, thiadiazole, and thiatriazole.
Other non-limiting examples of 5-membered-heteroaryl "groups include:
In certain embodiments, heteroaryl "is a 6-membered aromatic group containing 1, 2, or 3 nitrogen atoms (i.e., pyridinyl, pyridazinyl, triazinyl, pyrimidinyl, and pyrazinyl).
Non-limiting examples of 6-membered heteroaryl "groups having 1 or 2 nitrogen atoms include:
in certain embodiments, a —heteroaryl "is a 9 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.
Non-limiting examples of bicyclic-heteroaryl "groups include indole, benzofuran, isoindole, indazole, benzimidazole, azaindole, azapyridazine, purine, isobenzofuran, benzothiophene, benzisoxazole, benzisothiazole, benzoxazole and benzothiazole.
Other non-limiting examples of bicyclic-heteroaryl "groups include:
other non-limiting examples of bicyclic-heteroaryl "groups include:
other non-limiting examples of bicyclic-heteroaryl "groups include:
in certain embodiments, a —heteroaryl "is a 10 membered bicyclic aromatic group containing 1 or 2 atoms selected from nitrogen, oxygen, and sulfur.
Non-limiting examples of bicyclic-heteroaryl "groups include quinoline, isoquinoline, quinoxaline, phthalazine, quinazoline, cinnoline, and naphthyridine.
Other non-limiting examples of bicyclic-heteroaryl "groups include:
embodiments of "cycloalkyl
In certain embodiments, —cycloalkyl "is C 3 -C 8 Cycloalkyl, C 3 -C 7 Cycloalkyl, C 3 -C 6 Cycloalkyl radicals、C 3 -C 5 Cycloalkyl, C 3 -C 4 Cycloalkyl, C 4 -C 8 Cycloalkyl, C 5 -C 8 Cycloalkyl or C 6 -C 8 Cycloalkyl groups.
In certain embodiments, a cycloalkyl group has three carbons.
In certain embodiments, a cycloalkyl group has four carbons.
In certain embodiments, a cycloalkyl group has five carbons.
In certain embodiments, a cycloalkyl group has six carbons.
In certain embodiments, a cycloalkyl group has seven carbons.
In certain embodiments, a cycloalkyl group has eight carbons.
In certain embodiments, a cycloalkyl group has nine carbons.
In certain embodiments, a cycloalkyl group has ten carbons.
Non-limiting examples of cycloalkyl groups include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl.
Other non-limiting examples of cycloalkyl groups include indanes and tetrahydronaphthalenes, wherein the point of attachment of each group is on the cycloalkyl ring.
For example, the number of the cells to be processed,is a cycloalkyl "group.
However, the process is not limited to the above-described process,is an-aryl "group.
Other examples of cycloalkyl groups include
Embodiments of "heterocycles
In certain embodiments, a heterocycle refers to a cyclic ring having one nitrogen and 3, 4, 5, 6, 7, or 8 carbon atoms.
In certain embodiments, a heterocycle refers to a cyclic ring having one nitrogen and one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.
In certain embodiments, a heterocycle refers to a cyclic ring having two nitrogens and 3, 4, 5, 6, 7, or 8 carbon atoms.
In certain embodiments, a heterocycle refers to a cyclic ring having one oxygen and 3, 4, 5, 6, 7, or 8 carbon atoms.
In certain embodiments, a heterocycle refers to a cyclic ring having one sulfur and 3, 4, 5, 6, 7, or 8 carbon atoms.
Non-limiting examples of heterocycles include aziridine, oxirane, thietane, azetidine, 1, 3-diazacyclobutane, oxetane, and thietane.
Other non-limiting examples of heterocycles include pyrrolidine, 3-pyrroline, 2-pyrroline, pyrazolidine and imidazolidine.
Other non-limiting examples of heterocycles include tetrahydrofuran, 1, 3-dioxolane, tetrahydrothiophene, 1, 2-oxathiolane, and 1, 3-oxathiolane.
Other non-limiting examples of heterocycles include piperidine, piperazine, tetrahydropyran, 1, 4-dioxane, thiane, 1, 3-dithiane, 1, 4-dithiane, morpholine and thiomorpholine.
Other non-limiting examples of heterocycles include indoline, tetrahydroquinoline, tetrahydroisoquinoline and dihydrobenzofuran, wherein the point of attachment of each group is on the heterocycle.
For example, the number of the cells to be processed,is a heterocyclic "group. However, is->Is an-aryl "group. Non-limiting examples of heterocycles "further include:
other non-limiting examples of heterocycles include:
other non-limiting examples of heterocycles include:
non-limiting examples of heterocycles "further include:
non-limiting examples of heterocycles "further include:
other non-limiting examples of heterocycles include:
other non-limiting examples of heterocycles include:
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optional substituents
In certain embodiments, a moiety described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with one substituent.
In certain embodiments, a moiety described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with two substituents.
In certain embodiments, a moiety described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with three substituents.
In certain embodiments, a moiety described herein that may be substituted with 1, 2, 3, or 4 substituents is substituted with four substituents.
R 1 Embodiments of (1)
In certain embodiments, R 1 Selected from:
wherein each R' is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heterocycle, and heteroaryl.
In certain embodiments, R 1 Is a heterocyclic group optionally substituted with 1 or 2 substituents selected from R'.
In certain embodiments, R 1 Is a 6 membered heterocyclic group having one or two nitrogen atoms.
In certain embodiments, R 1 Is a 6 membered heterocyclic group having one or two oxygen atoms.
In certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
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in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
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in certain embodiments, R 1 Selected from:
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in certain embodiments, R 1 Selected from:
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in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from: in certain embodiments, R 1 Selected from:
In certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
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in certain embodiments, R 1 Selected from:
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in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
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in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
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in certain embodiments, R 1 Selected from:
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in certain embodiments, R 1 Selected from:
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in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
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in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
in certain embodiments, R 1 Selected from:
or a pharmaceutically acceptable salt thereof, wherein:
R 42 is hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, aliphatic or heteroaliphatic;
X 1 is NR 19 O or S;
X 2 is CH 2 Or C (O);
R 19 selected from alkyl, hydrogen, -C (O) NR 10 R 27 、-C(O)OR 27 、-C(O)R 27 Alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, heteroaryl; where valence permits, each of which is optionally selected from 1, 2, 3 or 4 independently of R 40 Substituted with substituents to form stable compounds;
R 20 is an aliphatic group including alkyl; and
R 23 is hydrogen, alkyl, halogen or haloalkyl.
In certain embodiments, R 1 Selected from:
or a pharmaceutically acceptable salt thereof.
Non-limiting embodiment of a: in certain embodiments, a is selected from:
in certain embodiments, a is selected from:
in certain embodiments, a is selected from:
in certain embodiments, a is selected from:
in certain embodiments, a is selected from:
in certain embodiments, a is selected from:
in certain embodiments, the compound of formula I has the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is thatAnd
X 4 selected from alkyl, aliphatic, aryl, heteroaryl, bicyclic, -NR 27 -、-NR 10 -、-CR 40 R 41 -、-O-、-C(O)-、-C(NR 27 )-、-C(S)-、-S(O)-、-S(O) 2 -, -S-, piperidine bonded to the tricyclic ring through N in the piperidine ring, a 6 membered heterocyclic ring having 2, 3 or 4 heteroatoms and a 4, 5 or 7 membered heterocyclic ring having 1, 2, 3 or 4 heteroatoms; where valence permits, each of which is optionally selected from 1, 2, 3 or 4 independently from the group consisting of non-hydrogen R 40 Substituted with substituents to form stable compounds.
In certain embodiments, the compounds of the present invention are selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compounds of the present invention are selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compounds of the present invention are selected from the group consisting of:
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or a pharmaceutically acceptable salt thereof.
Embodiment of X
In certain embodiments, X is a bond.
In certain embodiments, X is oxygen.
In certain embodiments, X is sulfur.
In certain embodiments, X is-NR 27 -。
In certain embodiments, X is-NR 10 -。
In certain embodiments, X is-CR 40 R 41 -。
In certain embodiments, X is-C (O) -.
In certain embodiments, X is-C (NR) 27 )-。
In certain embodiments, X is-C (S) -.
In certain embodiments, X is-S (O) 2 -。
In certain embodiments, X is-C (S) -.
In certain embodiments, X is-C (S) -.
In certain embodiments, X is-C (S) -.
In certain embodiments, X is a 5-membered aromatic heterocycle with the point of attachment in the 1,3 direction.
In certain embodiments, X is a 5-membered aromatic heterocycle with the point of attachment in the 1,2 direction.
In certain embodiments, X is a 6 membered aromatic heterocycle with the point of attachment in the 1,2 direction.
In certain embodiments, X is a 6 membered aromatic heterocycle with the point of attachment in the 1,3 direction.
In certain embodiments, X is a 6 membered aromatic heterocycle with the point of attachment in the 1,4 direction.
In certain embodiments, X is a 6 membered aromatic heterocycle with the point of attachment in the 1,3 direction.
In certain embodiments, X is a 5 membered heterocycle with the point of attachment in the 1,2 direction.
In certain embodiments, X is a 5 membered heterocycle with the point of attachment in the 1,3 direction.
In certain embodiments, X is a 6 membered heterocycle with the point of attachment in the 1,2 direction.
In certain embodiments, X is a 6 membered heterocycle with the point of attachment in the 1,3 direction.
In certain embodiments, X is a 6 membered heterocycle with the point of attachment in the 1,4 direction.
In certain embodiments, X is a bicyclic heterocycle having one heteroatom.
In certain embodiments, X is a bicyclic heterocycle having two heteroatoms.
In certain embodiments, X is a bicyclic heterocycle having one heteroatom, and one point of attachment is bonded to nitrogen and one point of attachment is bonded to carbon.
In certain embodiments, X is a bicyclic heterocycle having one heteroatom, and both points of attachment are bonded to carbon.
In certain embodiments, X is a bicyclic heterocycle having two heteroatoms, and both points of attachment are bonded to nitrogen.
In certain embodiments, X is a bicyclic heterocycle having two heteroatoms.
In certain embodiments, X is a fused bicycloalkane.
In certain embodiments, X is spiro-bicycloalkane.
In certain embodiments, X is selected from:
R 4 and R is 5 Embodiments of (1)
In certain embodiments, R 4 Is hydrogen.
In certain embodiments, R 4 Is an alkyl group.
In certain embodiments, R 4 Is fluorine.
In certain embodiments, R 4 Is chlorine.
In certain embodiments, R 4 Is bromine.
In certain embodiments, R 4 Is a haloalkyl group.
In certain embodiments, R 4 is-OR 10 。
In certain embodiments, R 4 is-SR 10 。
In certain embodiments, R 4 is-S (O) R 12 。
In certain embodiments, R 4 is-SO 2 R 12 。
In certain embodiments, R 4 is-NR 10 R 11 。
In certain embodiments, R 5 Is hydrogen.
In certain embodiments, R 5 Is an alkyl group.
In certain embodiments, R 5 Is a haloalkyl group.
In certain embodiments, R 5 is-OR 10 。
In certain embodiments, R 5 is-SR 10 。
In certain embodiments, R 5 is-S (O) R 12 。
In some casesIn embodiments, R 5 is-SO 2 R 12 。
In certain embodiments, R 5 is-NR 10 R 11 。
In certain embodiments, R 4 And R is 5 Selected from:
R 6 and R is 7 Embodiments of (1)
In certain embodiments, R 6 Is hydrogen.
In certain embodiments, R 6 Is an alkyl group.
In certain embodiments, R 6 Is fluorine.
In certain embodiments, R 6 Is chlorine.
In certain embodiments, R 6 Is bromine.
In certain embodiments, R 6 Is a haloalkyl group.
In certain embodiments, R 6 is-OR 10 。
In certain embodiments, R 6 is-SR 10 。
In certain embodiments, R 6 is-S (O) R 12 。
In certain embodiments, R 6 is-SO 2 R 12 。
In certain embodiments, R 6 is-NR 10 R 11 。
In certain embodiments, R 7 Is hydrogen.
In certain embodiments, R 7 Is an alkyl group.
In certain embodiments, R 7 Is fluorine.
In certain embodiments, R 7 Is chlorine.
In certain embodiments, R 7 Is bromine.
In some casesIn embodiments, R 7 Is a haloalkyl group.
In certain embodiments, R 7 is-OR 10 。
In certain embodiments, R 7 is-SR 10 。
In certain embodiments, R 7 is-S (O) R 12 。
In certain embodiments, R 7 is-SO 2 R 12 。
In certain embodiments, R 7 is-NR 10 R 11 。
In certain embodiments, R 6 And R is 7 Selected from:
R 10 and R is 11 Embodiments of (1)
In certain embodiments, R 10 And R is 11 Is hydrogen.
In certain embodiments, R 10 Is hydrogen.
In certain embodiments, R 11 Is hydrogen.
In certain embodiments, R 10 Is an alkyl group.
In certain embodiments, R 10 Is methyl.
In certain embodiments, R 10 Is an aliphatic group.
In certain embodiments, R 10 Is a haloalkyl group.
In certain embodiments, R 10 Is a heterocyclic ring.
In certain embodiments, R 10 Is aryl.
In certain embodiments, R 10 Is heteroaryl.
In certain embodiments, R 10 is-C (O) R 12 。
In certain embodiments, R 10 is-S (O) R 12 。
In certain embodiments, R 10 is-SO 2 R 12 。
In certain embodiments, R 11 Is an alkyl group.
In certain embodiments, R 11 Is methyl.
In certain embodiments, R 11 Is an aliphatic group.
In certain embodiments, R 11 Is a haloalkyl group.
In certain embodiments, R 11 Is a heterocyclic ring.
In certain embodiments, R 11 Is aryl.
In certain embodiments, R 11 Is heteroaryl.
In certain embodiments, R 11 is-C (O) R 12 。
In certain embodiments, R 11 is-S (O) R 12 。
In certain embodiments, R 11 is-SO 2 R 12 。
R 12 Embodiments of (1)
In certain embodiments, R 12 Is hydrogen.
In certain embodiments, R 12 Is an alkyl group.
In certain embodiments, R 12 Is a haloalkyl group.
In certain embodiments, R 12 Is a heterocyclic ring.
In certain embodiments, R 12 Is aryl.
In certain embodiments, R 12 Is heteroaryl.
In certain embodiments, R 12 is-NR 13 R 14 。
In certain embodiments, R 12 Is OR (OR) 13 。R 15 、R 16 And R is 17 Embodiments of (1)
In certain embodiments, R 15 Is a key.
In certain embodiments, R 15 Is an alkyl group.
In certain embodiments, R 15 Is an aliphatic group.
In certain embodiments, R 15 Is aryl.
In certain embodiments, R 15 Is a bicyclic ring.
In certain embodiments, R 15 Is an olefin.
In certain embodiments, R 15 Is an alkyne.
In certain embodiments, R 15 Is a haloalkyl group.
In certain embodiments, R 15 Is an alkoxy group.
In certain embodiments, R 15 Is heteroaryl.
In certain embodiments, R 15 Is a heterocyclic ring.
In certain embodiments, R 15 Is cycloalkyl.
In certain embodiments, R 15 Is a heteroaliphatic group.
In certain embodiments, R 15 is-NR 27 -。
In certain embodiments, R 15 is-NR 10 。
In certain embodiments, R 15 is-CR 40 R 41 -。
In certain embodiments, R 15 Is oxygen.
In certain embodiments, R 15 is-C (O) -.
In certain embodiments, R 15 is-C (S) -.
In certain embodiments, R 15 Is sulfur.
In certain embodiments, R 15 is-C (S) -.
In certain embodiments, R 15 is-OC (O) -.
In certain embodiments, R 15 is-C (O) O-.
In certain embodimentsWherein R is 15 is-C (O) NR 27 -。
In certain embodiments, R 15 is-NR 27 C(O)-。
In certain embodiments, R 15 is-NR 10 -。
In certain embodiments, R 15 Is a 6-membered aryl group with the point of attachment in the 1,2 direction.
In certain embodiments, R 15 Is a 6-membered aryl group with the point of attachment in the 1,3 direction.
In certain embodiments, R 15 Is a 6 membered aryl group with the point of attachment in the 1,4 direction.
In certain embodiments, R 15 Is a 6-membered aryl group with the point of attachment in the 1,2 direction.
In certain embodiments, R 15 Is heteroaryl with the point of attachment in the 1,2 direction.
In certain embodiments, R 15 Is heteroaryl with the point of attachment in the 1,2 direction.
In certain embodiments, R 15 Is aryl with the connection point in the 1,2 direction.
In certain embodiments, R 16 Is a key.
In certain embodiments, R 16 Is an alkyl group.
In certain embodiments, R 16 Is an aliphatic group.
In certain embodiments, R 16 Is aryl.
In certain embodiments, R 16 Is a bicyclic ring.
In certain embodiments, R 16 Is an olefin.
In certain embodiments, R 16 Is an alkyne.
In certain embodiments, R 16 Is a haloalkyl group.
In certain embodiments, R 16 Is an alkoxy group.
In certain embodiments, R 16 Is heteroaryl.
In certain embodiments, R 16 Is a impurityA ring.
In certain embodiments, R 16 Is cycloalkyl.
In certain embodiments, R 16 Is a heteroaliphatic group.
In certain embodiments, R 16 is-NR 27 -。
In certain embodiments, R 16 is-NR 10 。
In certain embodiments, R 16 is-CR 40 R 41 -。
In certain embodiments, R 16 Is oxygen.
In certain embodiments, R 16 is-C (O) -.
In certain embodiments, R 16 is-C (S) -.
In certain embodiments, R 16 Is sulfur.
In certain embodiments, R 16 is-C (S) -.
In certain embodiments, R 16 is-OC (O) -.
In certain embodiments, R 16 is-C (O) O-.
In certain embodiments, R 16 is-C (O) NR 27 -。
In certain embodiments, R 16 is-NR 27 C(O)-。
In certain embodiments, R 16 is-NR 10 -。
In certain embodiments, R 16 Is a 6-membered aryl group with the point of attachment in the 1,2 direction.
In certain embodiments, R 16 Is a 6-membered aryl group with the point of attachment in the 1,3 direction.
In certain embodiments, R 16 Is a 6 membered aryl group with the point of attachment in the 1,4 direction.
In certain embodiments, R 16 Is a 6-membered aryl group with the point of attachment in the 1,2 direction.
In certain embodiments, R 16 Is heteroaryl with the point of attachment in the 1,2 direction.
In certain embodiments, R 16 Is heteroaryl with the point of attachment in the 1,2 direction.
In certain embodiments, R 16 Is aryl with the connection point in the 1,2 direction.
In certain embodiments, R 17 Is a key.
In certain embodiments, R 17 Is an alkyl group.
In certain embodiments, R 17 Is an aliphatic group.
In certain embodiments, R 17 Is aryl.
In certain embodiments, R 17 Is a bicyclic ring.
In certain embodiments, R 17 Is an olefin.
In certain embodiments, R 17 Is an alkyne.
In certain embodiments, R 17 Is a haloalkyl group.
In certain embodiments, R 17 Is an alkoxy group.
In certain embodiments, R 17 Is heteroaryl.
In certain embodiments, R 17 Is a heterocyclic ring.
In certain embodiments, R 17 Is cycloalkyl.
In certain embodiments, R 17 Is a heteroaliphatic group.
In certain embodiments, R 17 is-NR 27 -。
In certain embodiments, R 17 is-NR 10 。
In certain embodiments, R 17 is-CR 40 R 41 -。
In certain embodiments, R 17 Is oxygen.
In certain embodiments, R 17 is-C (O) -.
In certain embodiments, R 17 is-C (S) -.
In certain embodiments, R 17 Is sulfur.
In certain embodiments, R 17 is-C (S) -.
In certain embodiments, R 17 is-OC (O) -.
In certain embodiments, R 17 is-C (O) O-.
In certain embodiments, R 17 is-C (O) NR 27 -。
In certain embodiments, R 17 is-NR 27 C(O)-。
In certain embodiments, R 17 is-NR 10 -。
In certain embodiments, R 17 Is a 6-membered aryl group with the point of attachment in the 1,2 direction.
In certain embodiments, R 17 Is a 6-membered aryl group with the point of attachment in the 1,3 direction.
In certain embodiments, R 17 Is a 6 membered aryl group with the point of attachment in the 1,4 direction.
In certain embodiments, R 17 Is a 6-membered aryl group with the point of attachment in the 1,2 direction.
In certain embodiments, R 17 Is heteroaryl with the point of attachment in the 1,2 direction.
In certain embodiments, R 17 Is heteroaryl with the point of attachment in the 1,2 direction.
In certain embodiments, R 17 Is aryl with the connection point in the 1,2 direction.
In certain embodiments, R 18 Is hydrogen.
In certain embodiments, R 18 Is halogen.
In certain embodiments, R 18 Is cyano.
In certain embodiments, R 18 is-C (O) OR 27 。
In certain embodiments, R 18 Is an alkyl group.
In certain embodiments, R 18 is-C (O) NR 10 R 27 。
In certain embodiments, R 18 is-NR 27 C(O)R 27 。
In certain embodiments, R 18 is-NR 10 R 27 。
In certain embodiments, R 18 Is SR (SR) 27 。
In certain embodiments, R 18 Is a haloalkyl group.
In certain embodiments, R 18 Is an alkoxy group.
In certain embodiments, R 18 Is aryl.
In certain embodiments, R 18 Is a heterocyclic ring.
In certain embodiments, R 18 Is an aliphatic group.
In certain embodiments, R 18 Is a heteroaliphatic group.
In certain embodiments, R 18 Is heteroaryl.
In certain embodiments, R 18 is-OR 27 。
R 19 Embodiments of (1)
In certain embodiments, R 19 Is an alkyl group.
In certain embodiments, R 19 Is hydrogen.
In certain embodiments, R 19 is-C (O) NR 10 R 27 。
In certain embodiments, R 19 is-C (O) OR 27 。
In certain embodiments, R 19 is-C (O) R 27 。
In certain embodiments, R 19 Is an olefin.
In certain embodiments, R 19 Is an alkyne.
In certain embodiments, R 19 Is a haloalkyl group.
In certain embodiments, R 19 Is an alkoxy group.
In certain embodiments, R 19 Is aryl.
In some implementationsIn the scheme, R 19 Is a heterocyclic ring.
In certain embodiments, R 19 Is an aliphatic group.
In certain embodiments, R 19 Is a heteroaliphatic group.
In certain embodiments, R 19 Is heteroaryl.
R 20 Embodiments of (1)
In certain embodiments, R 20 Is an aliphatic group.
In certain embodiments, R 20 Is an alkyl group.
In certain embodiments, R 20 Selected from:
R 23 embodiments of (1)
In certain embodiments, R 23 Is hydrogen.
In certain embodiments, R 23 Is fluorine.
In certain embodiments, R 23 Is bromine.
In certain embodiments, R 23 Is chlorine.
In certain embodiments, R 23 Is a haloalkyl group.
In certain embodiments, R 23 Selected from:
R 27 embodiments of (1)
In certain embodiments, R 27 Is hydrogen.
In certain embodiments, R 27 Is an alkyl group.
In certain embodiments, R 27 Is an arylalkyl group.
In certain embodiments, R 27 Is a heteroarylalkyl group.
In certain embodiments, R 27 Is an olefin.
In certain embodiments, R 27 Is an alkyne.
In certain embodiments, R 27 Is aryl.
In certain embodiments, R 27 Is heteroaryl.
In certain embodiments, R 27 Is a heterocyclic ring.
In certain embodiments, R 27 Is cycloalkyl.
In certain embodiments, R 27 Is an aliphatic group.
In certain embodiments, R 27 Is a heteroaliphatic group.
In certain embodiments, R 27 Selected from:
R 40 embodiments of (1)
In certain embodiments, R 40 Is hydrogen.
In certain embodiments, R 40 Is an aliphatic group.
In certain embodiments, R 40 Is a heteroaliphatic group.
In certain embodiments, R 40 Is cyano.
In certain embodiments, R 40 Is a nitro group.
In certain embodiments, R 40 Is an alkyl group.
In certain embodiments, R 40 Is fluorine.
In certain embodiments, R 40 Is chlorine.
In certain embodiments, R 40 Is bromine.
In certain embodiments, R 40 Is a haloalkyl group.
In certain embodiments, R 40 is-OR 10 。
In certain embodiments, R 40 is-SR 10 。
In certain embodiments, R 40 is-S (O) R 12 。
In certain embodiments, R 40 is-SO 2 R 12 。
In certain embodiments, R 40 is-NR 10 R 11 。
In certain embodiments, R 40 Selected from:
R 41 embodiments of (1)
In certain embodiments, R 41 Is an aliphatic group.
In certain embodiments, R 41 Is heteroaryl.
In certain embodiments, R 41 Is hydrogen.
In certain embodiments, R 41 Is an aliphatic group.
In certain embodiments, R 41 Is an aliphatic group.
In certain embodiments, R 41 Is an aliphatic group.
In certain embodiments, R 41 Selected from:
R 42 embodiments of (1)
In certain embodiments, R 42 Selected from:
non-limiting examples of compounds of formula I
Representative examples of compounds of formula I include:
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or a pharmaceutically acceptable salt thereof.
Non-limiting isotopic embodiments
In certain embodiments, the compound is isotopically labeled. In certain embodiments, independently selected from R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R'、R 19 、R 20 、R 23 、R 27 、R 40 、R 41 Or R is 42 Is isotopically labeled with an isotope permissible for 1, 2 or more valence states. In certain embodiments, the isotopic label is deuterium. In certain embodiments, at least one deuterium is placed on one atom The atom has a bond that is broken during the in vivo metabolism of the compound, or is one, two or three atoms that are remote from the metabolic bond (e.g., which may be referred to as α, β or γ, or primary, secondary or tertiary isotope effects). In another embodiment, the isotopic label is 13 C. In another embodiment, the isotopic label is 18 F。
III methods of treatment
Any tricyclic compound described herein may be used in an effective amount for treating a host, including a human, in need thereof, optionally in a pharmaceutically acceptable carrier to treat any of the disorders described herein. In certain embodiments, the method comprises administering an effective amount of an active compound as described herein, or a salt thereof, optionally including a pharmaceutically acceptable excipient, carrier, or adjuvant (i.e., a pharmaceutically acceptable composition), optionally in combination or alternation with other therapeutically active agent or agent.
In certain embodiments, the compounds of the invention selectively degrade IKZF2 and/or IKZF4 over one or more of IKZF1 and/or IKZF3 and/or IKZF 5.
In certain embodiments, the disorder treated by the compounds of the invention is an immunomodulatory disorder. In certain embodiments, the disorder treated by the compounds of the invention is mediated by angiogenesis. In certain embodiments, the disorder treated by the compounds of the invention is associated with the lymphatic system.
In certain embodiments, pharmaceutically acceptable salts of the compounds of the invention, optionally in pharmaceutical compositions as described herein, are used to degrade IKZF2 or IKZF4, which are mediators of disorders affecting patients, e.g., humans. The control of protein levels provided by any of the compounds of the invention provides for the treatment of a disease state or condition that is modulated by decreasing protein levels in cells (e.g., cells of a patient) or by decreasing levels of downstream proteins in cells via IKZF2 or IKZF 4. In certain embodiments, the method comprises administering an effective amount of a compound as described herein, optionally including a pharmaceutically acceptable excipient, carrier, adjuvant (i.e., pharmaceutically acceptable composition), optionally in combination or alternation with other therapeutically active agents or medicaments.
In certain embodiments, the compounds of the invention are useful for treating disorders including, but not limited to, benign growth, tumors, cancers, abnormal cell proliferation, immune disorders, inflammatory disorders, graft versus host rejection, viral infections, bacterial infections, amyloid-based proteinopathies, or fibrotic diseases.
The term "disease state" or-disorder "when used in connection with any compound refers to any disease state or disorder mediated by IKZF2 or IKZF4, such as cell proliferation, or any disease state or disorder mediated by proteins downstream of IKZF2 or IKZF4, and wherein degradation of such proteins in a patient may provide beneficial treatment or alleviation of symptoms to a patient in need thereof. In some cases, the disease state or condition may be cured.
In certain embodiments, a compound as described herein, or a corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, can be used in an effective amount to treat a host, e.g., a human, suffering from a lymphoma or lymphocyte or bone marrow cell proliferation disorder or abnormality. For example, the compounds described herein may be administered to a host suffering from hodgkin's lymphoma or non-hodgkin's lymphoma. For example, the host may have non-hodgkin lymphoma, such as, but not limited to: AIDS-related lymphoma; anaplastic large cell lymphoma; vascular immunoblastic lymphoma; blast NK-cell lymphoma; burkitt's lymphoma; burkitt-like lymphoma (small non-lytic cell lymphoma); diffuse small cell lymphoma (DSCCL); chronic lymphocytic leukemia/small lymphocytic lymphoma; cutaneous T cell lymphoma; diffuse large B cell lymphomas; enteropathy type T cell lymphoma; follicular lymphoma; gamma-delta T cell lymphoma of liver and spleen; lymphoblastic lymphoma; mantle cell lymphoma; edge area lymphoma; nasal T cell lymphoma; pediatric lymphomas; peripheral T cell lymphoma; primary central nervous system lymphomas; t cell leukemia; transforming lymphoma; treatment of associated T cell lymphomas; langerhans cell tissue cell proliferation; or Fahrenheit macroglobulinemia.
In another embodiment, a compound as described herein, or a corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, can be used in an effective amount to treat a host, such as a human, having hodgkin's lymphoma, for example, but not limited to: classical hodgkin's lymphoma of tuberous sclerosis (CHL); mixing cell CHL; lymphocyte depletion CHL; lymphocyte-enriched CHL; lymphocytic cell is the main type hodgkin lymphoma; or nodular lymphocytes based HL.
In another embodiment, a compound as described herein or a corresponding pharmaceutically acceptable salt, isotopic derivative or prodrug thereof can be used in an effective amount to treat a host, e.g., a human, suffering from an immunomodulatory disorder. Non-limiting examples of immunomodulatory disorders include: arthritis, lupus, celiac disease, sjogren's syndrome, polymyalgia rheumatica, multiple sclerosis, ankylosing spondylitis, type 1 diabetes, alopecia areata, vasculitis, and temporal arteritis.
In certain embodiments, the disorder treated with the compounds of the invention is a disorder associated with abnormal cell proliferation. Abnormal cell proliferation, particularly hyperproliferative, can be caused by a variety of factors including genetic mutation, infection, exposure to toxins, autoimmune diseases, and benign or malignant tumor induction.
Abnormal proliferation of B cells, T cells and/or NK cells can lead to a variety of diseases, such as cancer, proliferative diseases and inflammatory/immune diseases. Hosts, such as humans, suffering from any of these conditions can be treated with an effective amount of a compound as described herein to achieve a reduction in symptoms (palliative) or a reduction in potential disease (disease modifying agent).
In certain embodiments, a compound as described herein, or a corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, can be used in an effective amount for treating a host, e.g., a human, having a particular B-cell lymphoma or proliferative disease, not limited to: multiple myeloma; diffuse large B-cell lymphomas; follicular lymphoma; mucosal-associated lymphoid tissue lymphoma (MALT); small cell lymphocytic lymphomas; diffuse poorly differentiated lymphocytic lymphoma; mediastinum large B-cell lymphomas; lymph node marginal zone B cell lymphoma (NMZL); splenic Marginal Zone Lymphoma (SMZL); intravascular large B-cell lymphomas; primary exudative lymphomas; or lymphomatoid granulomatosis; b cell prolymphocytic leukemia; hairy cell leukemia; spleen lymphoma/leukemia, cannot be classified; diffuse red marrow small B cell lymphoma of the spleen; a hairy cell leukemia variant; lymphoplasmacytic lymphoma; heavy chain diseases, such as alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease; plasma cell myeloma; bone isolated plasmacytoma; bone exoplasmacytoma; primary cutaneous follicular central lymphoma; t cell/histiocyte enriched large B cell lymphomas; DLBCL associated with chronic inflammation; epstein-barr virus (EBV) +dlbcl in elderly; primary mediastinal (thymus) large B-cell lymphomas; primary skin DLBCL, leg; alk+ large B cell lymphomas; plasmablasts lymphoma; HHV 8-associated multicenter large B-cell lymphomas; kalman disease; b-cell lymphomas, which are not classified, have characteristics intermediate between diffuse large B-cell lymphomas; or B-cell lymphomas, which cannot be classified, have characteristics intermediate between diffuse large B-cell lymphomas and classical hodgkin lymphomas.
In certain embodiments, a compound as described herein, or a corresponding pharmaceutical salt, isotopic derivative, or prodrug thereof, can be used in an effective amount to treat a host, such as a human, T cell, or NK cell lymphoma, for example, but not limited to: anaplastic Lymphoma Kinase (ALK) positive, ALK negative anaplastic large cell lymphoma or primary anaplastic large cell lymphoma; vascular immunoblastic lymphoma; cutaneous T cell lymphomas, such as mycosis fungoides, szary syndrome, primary inter-cutaneous degenerative large cell lymphomas, primary cutaneous cd30+ T cell lymphoproliferative diseases; primary skin invasive epidermophilic cd8+ cytotoxic T cell lymphoma; primary cutaneous gamma-delta T cell lymphoma; primary cutaneous small/medium cd4+ T cell lymphomas and lymphomatoid papuloses; adult T cell leukemia/lymphoma (ATLL); blast NK cell lymphoma; enteropathy type T cell lymphoma; blood spleen gamma-delta T cell lymphoma; lymphoblastic lymphoma; nasal NK/T cell lymphomas; treatment of associated T cell lymphomas; such as lymphomas that occur after solid organ or bone marrow transplantation; t cell prolymphocytic leukemia; t cell large granule lymphocytic leukemia; NK cell chronic lymphoproliferative diseases; invasive NK cell leukemia; childhood systemic ebv+t cell lymphoproliferative disease (associated with chronic active EBV infection); hydroa vaccinia lymphoma; adult T cell leukemia/lymphoma; enteropathy-associated T cell lymphomas; hepatosplenic T cell lymphoma; or subcutaneous lipid membranitis-like T cell lymphoma.
In certain embodiments, a compound as described herein, or a corresponding pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, is useful in treating a host, such as a human, having leukemia. For example, the host may have acute or chronic leukemia of lymphocyte or bone marrow origin, such as, but not limited to: acute Lymphoblastic Leukemia (ALL); acute Myelogenous Leukemia (AML); chronic Lymphocytic Leukemia (CLL); chronic Myelogenous Leukemia (CML); juvenile myelomonocytic leukemia (JMML); hairy Cell Leukemia (HCL); acute promyelocytic leukemia (subtype of AML); large granular lymphocytic leukemia; or adult T cell chronic leukemia. In one embodiment, the patient has acute myelogenous leukemia, such as undifferentiated AML (M0); myeloblastic leukemia (M1; with/without minimal cell maturation); myeloblastic leukemia (M2; cell maturation); promyelocytic leukemia (M3 or M3 variation [ M3V ]); granulomonocytic leukemia (M4 or M4 variation with eosinophilia [ M4E ]); monocytic leukemia (M5); erythrocytic leukemia (M6); or megakaryocyte leukemia (M7).
There are many skin disorders associated with cell hyperproliferation. Psoriasis, for example, is a benign disease of human skin characterized by plaque covered by thickened scales. The disease is caused by an increase in proliferation of epidermal cells of unknown origin. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Other diseases caused by skin cell hyperproliferation include atopic dermatitis, lichen planus, warts, pemphigus vulgaris, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.
Other hyperproliferative cell disorders include vascular proliferation disorders, fibrotic disorders, autoimmune disorders, graft versus host rejection, tumors, and cancers.
Vascular proliferative disorders include angiogenic disorders and angiogenic disorders. Proliferation of smooth muscle cells during plaque formation in vascular tissue leads to restenosis, retinopathy and atherosclerosis, for example. Both cell migration and cell proliferation play a role in the formation of atherosclerotic lesions.
Fibrotic disorders are generally caused by abnormal formation of extracellular matrix. Examples of fibrotic disorders include cirrhosis and mesangial proliferative cell disorders. Cirrhosis is characterized by an increase in extracellular matrix components leading to the formation of liver scars. Cirrhosis can cause cirrhosis and other diseases. The increase in extracellular matrix leading to liver scarring can also be caused by viral infections such as hepatitis. Adipocytes appear to play a major role in cirrhosis.
Membranous disease is caused by abnormal proliferation of membranous cells. Mesangial hyperproliferative cell disorders include various human kidney diseases such as glomerulonephritis, diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndrome, transplant rejection and glomerulopathy.
Another disease with proliferative components is rheumatoid arthritis. Rheumatoid arthritis is generally considered to be an autoimmune disease, which is thought to be associated with the activity of autoreactive T cells, and is caused by autoantibodies against collagen and IgE production.
Other diseases that may include abnormal cellular proliferation components include Bechet syndrome, acute Respiratory Distress Syndrome (ARDS), ischemic heart disease, post-dialysis syndrome, leukemia, acquired immunodeficiency syndrome, vasculitis, lipotropenia, septic shock and general inflammation.
A compound as described herein, or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, can be used in an effective amount to treat a host, e.g., a human, suffering from a proliferative disease, e.g., myeloproliferative disease (MPD), polycythemia Vera (PV), essential Thrombocythemia (ET), myelodysplastic concomitant myelofibrosis (MMM), chronic myelomonocytic leukemia (CMML), eosinophilia (HES), systemic Mastocytosis (SMCD), and the like. In another embodiment, the compounds provided herein are useful for treating primary myelofibrosis, myelofibrosis following polycythemia vera, myelofibrosis following primary thrombocythemia, and secondary acute myelogenous leukemia.
In certain embodiments, a compound as described herein, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, can be used in an effective amount for treating a host, such as a human, suffering from myelodysplastic syndrome (MDS), such as, but not limited to: refractory thrombocytopenia with single line dysplasia, refractory anemia with cyclic iron granulomatous cells (RARS), refractory anemia with cyclic iron granulomatous-thrombocythemia (RARS-t), refractory thrombocytopenia with multiple line dysplasia (RCMD), RCMD with multiple line dysplasia and cyclic iron granulomatous cells (RCMD-RS), refractory amenorrhea with excessive primitive cells I (RAEB-I) and II (RAEB-II), 5 q-syndrome, refractory thrombocytopenia in children, and the like.
In one embodiment, the compounds of the invention may provide therapeutic effects by directly degrading Helios or Eos, which may alter transcriptional regulation of proteins downstream of Helios or Eos.
The term "neoplasia" or "cancer" is used to guide the pathological process of carcinogenesis or malignant tumor formation and growth, i.e., abnormal tissue that grows by cell proliferation, typically continues to grow faster than normal tissue and after cessation of stimulation that initiates new growth. Malignant tumors show a partial or complete lack of structural tissue and functional coordination with normal tissue, most invade surrounding tissue, metastasize to multiple sites, and are likely to recur and cause patient death after attempted resection unless adequately treated. As used herein, the term "neoplasia" is used to describe all cancerous disease states and includes or encompasses pathological processes associated with malignant blood borne, abdominal water borne, and solid tumors. Exemplary cancers that may be treated by the compounds of the present invention, alone or in combination with at least one additional anticancer agent, include: squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinoma and renal cell carcinoma, bladder carcinoma, intestinal cancer, breast carcinoma, cervical cancer, colon cancer, esophageal carcinoma, head cancer, kidney cancer, liver cancer, lung cancer, neck cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer; leukemia; benign and malignant lymphomas, in particular burkitt's lymphoma and non-hodgkin's lymphoma; benign and malignant melanoma; myeloproliferative diseases; sarcomas, including ewing's sarcoma, hemangiosarcoma, kaposi's sarcoma, liposarcoma, myosarcoma, peripheral nerve epithelioma, synovial sarcoma, glioma, astrocytoma, oligodendroglioma, ependymoma, glioblastoma, neuroblastoma, ganglioma, ganglioglioma, medulloblastoma, pineal tumor, meningioma, fibroneuroma, and schwannoma; intestinal cancer, breast cancer, prostate cancer, cervical cancer, uterine cancer, lung cancer, ovarian cancer, testicular cancer, thyroid cancer, astrocytoma, esophageal cancer, pancreatic cancer, gastric cancer, liver cancer, colon cancer, melanoma; carcinoma sarcoma, hodgkin's disease, wilms' tumor, and teratocarcinoma. Other cancers that may be treated using compounds according to the present invention include, for example, T-lineage acute lymphoblastic leukemia (T-ALL), T-lineage lymphoblastic lymphoma (T-LL), peripheral T-cell lymphoma, adult T-cell leukemia, pre-BALL, pre-B lymphoma, large B cell lymphoma, burkitt's lymphoma, B cell ALL, philadelphia chromosome positive ALL, and Philadelphia chromosome positive CML.
Other cancers that may be treated using the compounds disclosed in accordance with the present invention include, for example, acute myeloid leukemia, acute Lymphoblastic Leukemia (ALL), acute Myelogenous Leukemia (AML), adenocarcinoma, adenosarcoma, adrenal carcinoma, adrenocortical carcinoma, anal carcinoma, anaplastic astrocytoma, angiosarcoma, appendiceal carcinoma, astrocytoma, basal cell carcinoma, B-cell lymphoma, cholangiocarcinoma, bladder carcinoma, bone cancer, bone marrow carcinoma, intestinal cancer, brain stem glioma, breast cancer, triple (estrogen, progestin and HER-2) negative breast cancer, double negative breast cancer (two of estrogen, progestin and HER-2 are negative), single negative (one of estrogen, progestin and HER-2 is negative), estrogen receptor positive, HER2 negative breast cancer, estrogen receptor positive breast cancer, metastatic breast cancer, luminal a breast cancer, luminal B breast cancer, HER2 negative breast cancer, HER2 positive or negative breast cancer, progestin receptor positive breast cancer, recurrent breast cancer, carcinoid tumor, cervical cancer, cholangiocarcinoma, chondrosarcoma, chronic Lymphocytic Leukemia (CLL), chronic Myelogenous Leukemia (CML), colon cancer, colorectal cancer, craniopharyngeal tumor, cutaneous lymphoma, cutaneous melanoma, diffuse astrocytoma, ductal Carcinoma In Situ (DCIS), endometrial cancer, ependymoma, epithelioid sarcoma, esophageal cancer, ewing sarcoma, extrahepatic cholangiocarcinoma, ocular cancer, fallopian tube cancer, fibrosarcoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor glioblastoma multiforme (GBM), glioma, hairy cell leukemia, head and neck cancer, vascular endothelial tumor, hodgkin's lymphoma, hypopharynx cancer, invasive Ductal Carcinoma (IDC), invasive Lobular Carcinoma (ILC), inflammatory Breast Cancer (IBC), intestinal cancer, intrahepatic bile duct cancer, invasive/invasive breast cancer, islet cell carcinoma, jaw bone cancer, kaposi's sarcoma, renal carcinoma, laryngeal carcinoma, leiomyosarcoma, pia metastatic tumor, leukemia, lip cancer, liposarcoma, liver cancer, small leaf carcinoma in situ, low-grade astrocytoma, lung cancer, lymph node cancer, lymphoma, male breast cancer, medullary carcinoma, medulloblastoma, melanoma, meningioma, merck cell carcinoma, mesenchymal chondrosarcoma, mesenchymal, mesothelioma metastatic breast cancer metastatic melanoma metastatic cervical squamous carcinoma, mixed glioma, single-skin teratoma, oral cancer, mucous carcinoma, mucosal melanoma, multiple myeloma, mycosis, myelodysplastic syndrome, nasal cancer, nasopharyngeal carcinoma, cervical cancer, neuroblastoma, neuroendocrine tumor (NET), non-Hodgkin lymphoma, non-small cell lung carcinoma (NSCLC), oat cell carcinoma, eye cancer, ocular melanoma, oligodendroglioma, oral cancer, oropharyngeal cancer, osteogenic sarcoma, osteosarcoma, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian primary peritoneal carcinoma, ovarian chordal mesoma, paget's disease, pancreatic cancer, papillary carcinoma, sinus cancer, parathyroid carcinoma, pelvic carcinoma, penile carcinoma, peripheral nerve carcinoma, peritoneal carcinoma, pharyngeal carcinoma, pheochromocytoma, hair cell astrocytoma, pineal region tumor, pineal cytoma, pituitary carcinoma, primary Central Nervous System (CNS) lymphoma, prostate cancer, rectal cancer, renal cell carcinoma, renal pelvis carcinoma, rhabdomyosarcoma, salivary gland carcinoma, soft tissue sarcoma, osteosarcoma, sarcoma, sinus cancer, skin cancer, small Cell Lung Cancer (SCLC), small intestine cancer, spinal cord cancer, squamous cell carcinoma, gastric cancer, synovial sarcoma, T cell lymphoma, testicular cancer, laryngeal cancer, thymoma/thymus cancer, thyroid cancer, tongue cancer, tonsil cancer, transitional cell carcinoma, fallopian tube cancer, tubular cancer, undiagnosed cancer, ureter cancer urethra cancer, uterine adenocarcinoma, uterine carcinoma, uterine sarcoma, vaginal carcinoma, vulvar carcinoma, T cell line acute lymphoblastic leukemia (T-ALL), T cell line lymphoblastic lymphoma (T-LL), peripheral T cell lymphoma, adult T cell leukemia, pre-BALL, pre-B lymphoma, large B cell lymphoma, burkitts lymphoma, B cell ALL, philadelphia chromosome positive CML, young myelomonocytic leukemia (JMML), acute promyelocytic leukemia (a subtype of AML), large granule lymphoblastic leukemia, adult T cell chronic leukemia, diffuse large B cell lymphoma, follicular lymphoma; mucosa-associated lymphohistiolymphoma (MALT), small cell lymphocytic lymphoma, mediastinum large B-cell lymphoma, and lymph node marginal zone B-cell lymphoma (NMZL); splenic Marginal Zone Lymphoma (SMZL); intravascular large B-cell lymphomas; primary exudative lymphomas; or lymphomatoid granulomatosis; b cell prolymphocytic leukemia; spleen lymphoma/leukemia, which is not classified, diffuse red marrow small B cell lymphoma; lymphoplasmacytic lymphoma; heavy chain diseases, such as alpha heavy chain disease, gamma heavy chain disease, mu heavy chain disease, plasma cell myeloma, bone solitary plasmacytoma; bone exoplasmacytoma; primary skin follicular central lymphoma, T cell/histiocyte enriched large B cell lymphoma, DLBCL associated with chronic inflammation; epstein-barr virus (EBV) +dlbcl in elderly; primary mediastinal (thymus) large B-cell lymphomas; primary skin DLBCL, leg, alk+ large B-cell lymphoma, plasmablasts; large B cell lymphomas caused by HHV 8-associated multicenter, castleman disease; b-cell lymphomas, which are not classified, have characteristics between diffuse large B-cell lymphomas, or B-cell lymphomas, which are not classified, have characteristics between diffuse large B-cell lymphomas and classical hodgkin lymphomas. In certain embodiments, the disorder is adenoid cystic carcinoma. In certain embodiments, the disorder is a NUT midline cancer.
In another embodiment, a compound as described herein, or a pharmaceutically acceptable salt, isotopic derivative, or prodrug thereof, can be used in an effective amount to treat a host, such as a human, having an autoimmune disease. Examples include, but are not limited to: acute Disseminated Encephalomyelitis (ADEM); addison's disease; no gammaglobulinemia; alopecia areata; amyotrophic lateral sclerosis (also known as luglick disease; motor neuron disease); ankylosing spondylitis; antiphospholipid syndrome; anti-synthetase syndrome; atopic allergy; atopic dermatitis; autoimmune aplastic anemia; autoimmune arthritis; autoimmune cardiomyopathy; autoimmune bowel disease; autoimmune granulocytopenia; autoimmune hemolytic anemia; autoimmune hepatitis; autoimmune hypoparathyroidism; autoimmune inner ear disease; autoimmune lymphoproliferative syndrome; autoimmune myocarditis; autoimmune pancreatitis; autoimmune peripheral neuropathy; autoimmune ovarian failure; autoimmune multiple endocrine syndrome; autoimmune dermatitis of progesterone; autoimmune thrombocytopenic purpura; autoimmune thyroid disease; autoimmune urticaria; autoimmune uveitis; autoimmune vasculitis; balo disease/Balo concentric circle sclerosis; behcet's disease; berger's disease; bikes taff encephalitis; braw syndrome; bullous pemphigoid; cancer; kalman disease; celiac disease; right disease; chronic inflammatory demyelinating polyneuropathy; chronic inflammatory demyelinating polyneuropathy; chronic obstructive pulmonary disease; chronic recurrent multifocal osteomyelitis; churg-Strauss syndrome; cicatricial pemphigoid; kegen syndrome; cold lectin disease; supplemental ingredient 2 deficiency; contact dermatitis; craniofacial arteritis; CREST syndrome; crohn's disease; cushing's syndrome; skin leukocyte-disrupting vasculitis; degodisease; dercum disease; dermatitis herpetiformis; dermatomyositis; type 1 diabetes; diffuse systemic sclerosis of the skin; discoid lupus erythematosus; de leisler syndrome; drug-induced lupus; eczema; endometriosis; arthritis associated with attachment points; eosinophilic fasciitis; eosinophilic gastroenteritis; eosinophilic pneumonia; epidermolysis bullosa; erythema nodosum; erythroblastosis of the fetus; basic mixed cryoglobulinemia; elwin syndrome; extrinsic and intrinsic reactive airway diseases (asthma); the progression of fibrodysplasia ossificans; fibrosing alveolitis (or idiopathic pulmonary fibrosis); gastritis; pemphigoid of the gastrointestinal tract; glomerulonephritis; goodpasture syndrome; graves' disease; guillain-Barre syndrome (GBS); hashimoto's encephalopathy; hashimoto thyroiditis; hemolytic anemia; allergic purpura; herpes gestation (pemphigoid gestation); hidradenitis suppurativa; hous-stoneley syndrome; hypogammaglobulinemia; idiopathic inflammatory demyelinating diseases; idiopathic pulmonary fibrosis; idiopathic thrombocytopenic purpura; igA nephropathy; immune glomerulonephritis; immune nephritis; immune pneumonia; inclusion body myositis; inflammatory bowel disease; interstitial cystitis; juvenile idiopathic arthritis is also known as juvenile rheumatoid arthritis; kawasaki disease; lambert-eaton muscle weakness syndrome; leukocyte-fragmenting vasculitis; moss planus; lichen sclerosis; linear IgA disease (LAD); lupus hepatitis is also known as autoimmune hepatitis; lupus erythematosus; ma Jide syndrome; polyangiitis under microscope; miller-Fisher syndrome; mixed connective tissue disease; morphea; mucha-Habermann disease is also known as acute acne-like lichen-like pityriasis; multiple sclerosis; myasthenia gravis; myositis; meniere's disease; narcolepsy; neuromyelitis optica (also devek's disease); neuromuscular rigidity; ocular cicatricial pemphigoid; ocular myoclonus syndrome; ademetic thyroiditis; palindromic rheumatism; PANDAS (streptococcal-related pediatric autoimmune neuropsychiatric disease); paraneoplastic cerebellar degeneration; paroxysmal Nocturnal Hemoglobinuria (PNH); pari Luo Mba lattice syndrome; tonsillitis; pastician-turner syndrome; pemphigus vulgaris; peripheral encephalomyelitis; pernicious anemia; poe ms syndrome; polyarteritis nodosa; rheumatalgia; polymyositis; primary biliary cirrhosis; primary sclerosing cholangitis; progressive inflammatory neuropathy; psoriasis; psoriatic arthritis; pure red blood cell dysgenesis; pyoderma gangrenosum; a brain disease of Las Mu Sen; reynolds phenomenon; rayleigh syndrome; recurrent polychondritis; restless legs syndrome; retroperitoneal fibrosis; rheumatic fever; rheumatoid arthritis; sarcoidosis; schizophrenia; schmitt syndrome; schniter syndrome; scleritis; scleroderma; sclerosing cholangitis; serum sickness; sjogren syndrome; spinal arthropathy; stiff human syndrome; still disease; subacute Bacterial Endocarditis (SBE); soxak syndrome; shewlett syndrome; sedney disease; sympathogenic ophthalmia; systemic lupus erythematosus; high an arteritis; temporal arteritis (also known as giant cell arteritis "); thrombocytopenia; tolosa-Hunt syndrome; transverse myelitis; ulcerative colitis; undifferentiated connective tissue disease; indifferent spinal arthropathy; urticaria vasculitis; vasculitis; vitiligo; viral diseases such as Epstein Barr Virus (EBV), hepatitis b, hepatitis c, HIV, HTL V1, varicella-zoster virus (VZV) and Human Papilloma Virus (HPV); or wegener granulomatosis. In some embodiments, the autoimmune disease is an allergic disease, including those from asthma, food allergy, atopic dermatitis, chronic pain, and rhinitis.
Skin contact allergies and asthma are just two examples of immune responses that may be associated with significant morbidity. Other include atopic dermatitis, eczema, sjogren's syndrome, including sjogren's syndrome secondary keratoconjunctivitis, alopecia areata, allergic reactions to arthropod bite reactions, crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative conjunctivitis, cutaneous systemic lupus erythematosus, scleroderma, vaginitis, proctitis and drug eruptions. These conditions may lead to any one or more of the following symptoms or signs: itching, swelling, redness, blisters, crusting, ulcers, pain, desquamation, cracking, hair loss, scars or exudation of liquids involving the skin, eyes or mucous membranes.
In atopic dermatitis and eczema in general, immune-mediated infiltration of leukocytes (particularly infiltration of monocytes, lymphocytes, neutrophils and eosinophils) into the skin plays an important role in the pathogenesis of these diseases. Chronic eczema is also associated with significant hyperproliferation of the epidermis. Immune-mediated leukocyte infiltration also occurs in sites other than the skin, such as the airways of asthmatic patients and the lacrimal glands of keratoconjunctivitis sicca eyes.
A compound as described herein, or a pharmaceutically acceptable salt, isotopic variant, or prodrug thereof, can be used in an effective amount to treat a host, e.g., a human, suffering from a skin disorder, e.g., psoriasis (e.g., psoriasis vulgaris), atopic dermatitis, rash, skin irritation, skin allergy (e.g., contact dermatitis or allergic contact dermatitis). For example, certain substances (including certain drugs) can cause skin irritation when used topically. In some embodiments, the dermatological disorders are treated by topical application of a compound known in the art in combination with a compound disclosed herein. In one non-limiting embodiment, the compounds of the invention are useful as topical agents for the treatment of contact dermatitis, atopic dermatitis, eczematous dermatitis, psoriasis, sjogren's syndrome, including keratoconjunctivitis sicca secondary to sjogren's syndrome, alopecia areata, allergic reactions due to arthropod bite reactions, crohn's disease, aphthous ulcers, iritis, conjunctivitis, keratoconjunctivitis, ulcerative colitis, asthma, allergic asthma, cutaneous lupus erythematosus, scleroderma, vaginitis, proctitis and drug eruptions. The new method can also be used for reducing infiltration of malignant leucocytes into skin in diseases such as mycosis.
Disease states of conditions which may be treated using the compounds according to the invention include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, fibroses, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorders, obesity, ametropia, infertility, angelman syndrome, kanten's disease, celiac disease, charcot-Marie-Tooth disease, cystic fibrosis, duchenne muscular dystrophy, hemochromatosis, hemophilia, kehner syndrome, neurofibromatosis, phenylketonuria, polycystic kidney disease PKD 1) or 2 (PKD 2) Prader-Willi syndrome, sickle cell disease, tay-Sachs disease, tener syndrome.
Other disease states or conditions that may be treated by the compounds of the invention include Alzheimer's disease, amyotrophic lateral sclerosis (Lou Gehrig's disease), anorexia nervosa, anxiety, atherosclerosis, attention deficit hyperactivity disorder, autism, bipolar disorder, chronic fatigue syndrome, chronic obstructive pulmonary disease, crohn's disease, coronary heart disease, dementia, depression, type 1 diabetes, type 2 diabetes, epilepsy, guillain-Barre syndrome, irritable bowel syndrome, lupus, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, parkinson's disease, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans, tourette's syndrome, vasculitis.
Other disease states or conditions treatable by the compounds of the invention include ceruloplasmin, cartilage formation type II, achondroplasia, cranial deformity, gaucher disease type 2, acute intermittent porphyrin, kanwan's disease, adenomatous polyposis E.coli, ALA dehydratase deficiency, adenylate lyase deficiency, adrenogenital syndrome, adrenoleukodystrophy, ALA-D porphyrin, ALA dehydratase deficiency, alkaline aciduria, alexander's disease, alkaline acidosis, alpha 1-antitrypsin deficiency, alpha 1 protease inhibitor, emphysema, amyotrophic lateral sclerosis, alexander's disease ALA dehydratase deficiency, anderson-Fabry disease, androgen insensitivity syndrome, anemic body vessel keratoma, retinal hemangiomatosis (von Hippel-Lindau disease) Apert syndrome, arachnoid disease (equine syndrome), stickler syndrome, multiple joint relaxation (Ehler-lax #s), pulmonary hypertension, pulmonary disease, and other diseaseshoff disease, type II neurofibromatosis, beare-Stevenson's gyrate scalp syndrome, familial mediterranean fever, benjamin syndrome, beta-thalassemia, bilateral auditory neurofibromatosis (type II neurofibromatosis), factor V Leiden thrombophilia, bloch-Sulzberger syndrome (pigment incontinence), bloom syndrome, X-linked iron granulocyte anemia, bonnevie-Ullrich syndrome (Turner syndrome), bonneville disease (tuberous sclerosis), prion disease, birt-Hogg-Dub's syndrome, brittle bone disease (osteogenesis imperfecta), thumb-hallux syndrome (RubINSTRIN-Taybi syndrome), bronze diabetes/bronze liver cirrhosis (hemochromatosis), myelogenous muscular atrophy (Kennedy disease), spinal muscular atrophy (Kennel disease) berg-ger Lu Cizeng syndrome (lipoprotein lipase deficiency), CGD chronic granuloma, campomelic dysplasia, biotin deficiency, cardiomyopathy (Noonan syndrome), cat crying, CAVD (congenital deficiency of vas deferens), caylor heart face syndrome (CBAVD), CEP (congenital erythropoiesis porphyria), cystic fibrosis, congenital hypothyroidism, cartilage dystrophy syndrome (chondrogenesis imperfecta), earvertebral mastocytosis, lesch-Nyhan syndrome, galactosylemia, ehlers-Danlos syndrome, lethal bone hypoplasia, coffin-Lowry syndrome, cockayne syndrome, (familial adenomatous polyposis), congenital erythropoiesis porphyria, congenital heart disease, hyperlipoproteinemia/congenital hyperhemoglobinemia, chondrohypoplasia, X-linked iron particle young cell anemia, connective tissue disease, nose cone malformation facial anemia, thalassemia (beta-thalassemia), copper storage disease (Wilson's disease), copper transport disease (Menkes's disease), hereditary manure porphyrin disease, cowden syndrome, craniofacial joint disorder (Crouzon syndrome), creutzfeldt-Jakob disease (prion disease), cockayne syndrome, cowden syndrome, curchmann-Batten-Steinart syndrome (myotonic dystrophy), beare-Stevenson's gyrate scalp syndrome, primary hyperoxalic acid urea, spinal metaphysis (Strudwick type), muscular dystrophy, dunalis and Beckel (D), sub-sepia syndrome, degenerative neurological diseases including Grouy syndrome and Derine-Sotten disorder, spinal muscular atrophy, spinal cord developmental disorder, spinal cord injury, and the like Type V, androgen insensitivity syndrome, diffuse spheroid sclerosis (Krabbe's disease), digella syndrome, dihydrotestosterone receptor deficiency, androgen insensitivity syndrome, down's syndrome, dwarfism, erythropoiesis protoporphyrin, erythropoiesis 5-aminolevulinic acid synthetase deficiency, erythropoiesis porphyria, erythropoiesis protoporphyrin, erythropoiesis uroporphyria, laborious Dexigans-familial bursa-pastoris, delayed skin porphyria, familial pressure sensitive neuropathy, primary pulmonary arterial hypertension (PPH), pancreatic fibrocystic disease, fragile X syndrome, galactosyl syndrome, hereditary brain disease, giant cell hepatitis (neonatal hemochromatosis), gronblad-Strandberg syndrome (elastic pseudoxanthoma), gunther's disease (congenital erythropoiesis porphyria), hemochromatosis, halgren's syndrome, erythropoiesis red blood anemia, hepadultherin-hepadulthood, huppel-hypovolemia, huntin's disease, huntington's disease, including X-linked severe combined immunodeficiency, insley-Astley syndrome, jackson-Weiss syndrome, joubert syndrome, lesch-Nyhan syndrome, jackson-Weiss syndrome, renal diseases including homooxalic acid urea, klinefelter syndrome, kniest dysplasia, lacuna dementia, langer-Saldino cartilage formation, ataxia telangiectasia, lindgy syndrome, lysyl hydroxylase deficiency, machado-Joseph disease, metabolic disorders including Kniest dysplasia, ma Fanzeng syndrome, dyskinesia, mowat-Wilson syndrome, cystic fibrosis, muenke syndrome, multiple neurofibromatosis, nance-Insley syndrome, nance-Sweeney chondrodysplasia, niemann-Pick disease, noack syndrome (Pfeiffer syndrome), osler-Weber-Rendu disease, peutz-Jeghers syndrome, polycystic kidney disease, multiple skeletal fibrous dysplasia (McCune-align syndrome), peutz-Jeghers syndrome, prader-Labhart-Willi syndrome, hemochromatosis, primary hyperuricemia syndrome (Lesch-Nyhan syndrome), primary pulmonary hypertension, primary degenerative dementia, prion disease, premature senility (Hutchinson Gilford early stage) Failure syndrome), progressive chorea, chronic hereditary (huntington's disease), progressive muscular atrophy, spinal muscular atrophy, propionic acid, protoporphyria, proximal myotonic dystrophy, pulmonary hypertension, PXE (pseudoxanthoma), rb (retinoblastoma), recklinghausen's disease (neurofibromatosis type I), recurrent polyase serositis, retinal disease, retinoblastoma, rett syndrome, RFALS type 3, ricker syndrome, riley-Day syndrome, roussy-Levy syndrome, severe achondroplasia with delayed development and acanthosis nigricans (SADDAN), li-frauaui syndrome, sarcoma, breast cancer, leukemia and adrenal gland (SBLA) syndrome, tuberous sclerosis (tuberous sclerosis), SDAT, SED congenital (congenital epiphyseal dysplasia), SED stromatosis (epiphysis), stradwick type), SEDc (congenital epiphyseal dysplasia) SEMD, strudwick (bone awl bone end dysplasia, stradwick type), shprinzen syndrome, skin pigmentation, smith-Lemli-Opitz syndrome, south african hereditary porphyria (varix porphyria), infantile ascending hereditary spastic paralysis, speech and communication disorders, sphingolipid deposition, tax saxosis, spinocerebellar ataxia, stickler syndrome, stroke, androgen insensitivity syndrome, tetrahydrobiopterin deficiency, beta-thalassemia, thyroid disease, megaloblastic neuropathy (hereditary neuropathy with pressure paralysis), treacher Collins syndrome, triple X syndrome (triple X syndrome), trisomy 21 syndrome (Down syndrome), trisomy X syndrome, VHL syndrome (von Hippel-Lindau disease), vision disorder and blindness Syndrome), vrolik disease, waadenburg syndrome, warburg Sjo Fledelius syndrome, wolf-Hirschhorn syndrome, wolff periodic disease, weissenbacher-Zweym uller syndrome, and pigment xeroderma, and the like.
In certain embodiments, a method of treating solid tumors, such as non-small cell lung cancer or melanoma, is provided comprising administering to a patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition for treating multiple myeloma. In another embodiment, a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, is used in a method of treating a solid tumor, such as non-small cell lung cancer or melanoma, optionally in a pharmaceutically acceptable carrier to form a composition, wherein the method comprises administering the compound to a patient.
In certain embodiments, a method of controlling progression of multiple myeloma is provided comprising administering to a patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier, to form a composition. In another embodiment, a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, is optionally in a pharmaceutically acceptable carrier to form a composition for use in a method of controlling the progression of multiple myeloma, wherein said method comprises administering said compound to a patient.
In certain embodiments, the solid tumor is resistant to treatment with an anti-PD-1 agent.
In certain embodiments, solid tumors are refractory to treatment with anti-PD-1 agents.
In certain embodiments, the solid tumor is resistant to treatment with an anti-PD-L1 agent.
In certain embodiments, solid tumors are refractory to treatment with anti-PD-L1 agents.
In one embodiment, a method of controlling progression of multiple myeloma is provided comprising administering to a patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier, to form a composition. In another embodiment, a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, is used in a method for treating multiple myeloma, optionally in a pharmaceutically acceptable carrier, wherein said method comprises administering said compound to a patient.
In certain embodiments, a method of controlling progression of multiple myeloma is provided comprising administering to a patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier, to form a composition. In another embodiment, a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, is optionally in a pharmaceutically acceptable carrier to form a composition for use in a method of controlling the progression of multiple myeloma, wherein said method comprises administering said compound to a patient.
In certain embodiments, a method of inducing a therapeutic response in a patient suffering from multiple myeloma is provided, as assessed by the international unified response standard (IURC) for multiple myeloma (described in Durie b.g.m. et al, international unified response standard for multiple myeloma, "Leukemia 2006,10 (10): 1-7), comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier, to form a composition.
In another embodiment, a method is provided to achieve a strict complete response, complete response or very good partial response, such as the assessment of multiple myeloma by IURC in a patient suffering from multiple myeloma, comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analogue or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
In another embodiment, a method is provided to achieve an increase in overall survival, progression-free survival, event-free survival, processing time, or disease-free survival in a patient suffering from multiple myeloma comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
In another embodiment, there is provided a method of achieving increased overall survival in a patient suffering from multiple myeloma comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier, to form a composition.
In another embodiment, a method of achieving increased progression free survival in a patient suffering from multiple myeloma is provided, the method comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier, to form a composition.
In another embodiment, a method of achieving increased event-free survival in a patient suffering from multiple myeloma is provided, the method comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier, to form a composition.
In another embodiment, a method of achieving increased time of progression in a patient suffering from multiple myeloma is provided comprising administering to the patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier, to form a composition.
In another embodiment, a method of achieving increased disease-free survival in a patient suffering from multiple myeloma is provided, comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier, to form a composition.
In addition to patients who have not previously been treated, methods of treating patients who have previously been treated for multiple myeloma but who have not responded to standard therapy are also provided. In addition to non-operated patients, other methods are provided for treating patients who have been operated on in an attempt to treat multiple myeloma. In addition to those patients who have not received transplantation therapy, methods of treating patients who have previously received transplantation therapy are provided.
The compounds described herein are useful for treating or controlling relapsed, refractory or drug-resistant multiple myeloma. In some embodiments, the multiple myeloma is primary, secondary, three, four, or five relapses. In certain embodiments, the compounds described herein may be used to reduce, maintain, or eliminate Minimal Residual Disease (MRD).
Types of multiple myeloma that can be treated with the compounds described herein include, but are not limited to: monoclonal Gammaglobulosis (MGUS) of unknown significance; low-risk, medium-risk or high-risk multiple myeloma; newly diagnosed multiple myeloma, including low, medium or high risk newly diagnosed multiple myeloma); multiple myeloma meeting and not meeting the transplantation condition; smoldering (inert) multiple myeloma (including low, medium or high-risk smoldering multiple myeloma); active multiple myeloma; isolated plasmacytomas; plasma cell leukemia; multiple myeloma of the central nervous system; light chain myeloma; non-secretory myeloma; immunoglobulin D myeloma; and immunoglobulin E myeloma.
In some embodiments, the compounds described herein are useful for treating or controlling multiple myeloma characterized by genetic abnormalities, such as, but not limited to: cyclin D translocations (e.g., t (11; 14) (q 13; q 32), t (6; 14) (p 21; 32), t (12; 14) (p 13; q 32), or t (6; 20)); MMSET translocation (e.g., t (4; 14) (p 16; q 32), MAF translocation (e.g., t (14; 16) (q 32; a 32), t (20; 22), t (16; 22) (q 11; q 13), or t (14; 20) (q 32; q 11), or other chromosomal factors (e.g., deletion of chromosome 17p13 or chromosome 13; del (17/17 p), non-hypersaline, and gain (1 q)).
In certain embodiments, a method for treating or controlling multiple myeloma is provided comprising administering to a patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition, as an induction therapy.
In certain embodiments, a method for treating or controlling multiple myeloma is provided comprising administering to a patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable form, a carrier-forming composition, as a consolidation therapy.
In certain embodiments, a method for treating or controlling multiple myeloma is provided comprising administering to a patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable form, a carrier-forming composition, as maintenance therapy.
In certain embodiments, the multiple myeloma is plasma cell leukemia.
In certain embodiments, the multiple myeloma is a high-risk multiple myeloma. In some embodiments, the high-risk multiple myeloma is recurrent or refractory. In certain embodiments, the high-risk multiple myeloma recurs within 12 months of the first treatment. In another embodiment, high-risk multiple myeloma is characterized by genetic abnormalities, such as one or more of del (17/17 p) and t (14; 16) (q 32; q 32). In some embodiments, the high-risk multiple myeloma recurs or is refractory to one, two, or three previous treatments.
In certain embodiments, the multiple myeloma has a p53 mutation. In certain embodiments, the p53 mutation is a Q331 mutation. In certain embodiments, the p53 mutation is an R273H mutation. In certain embodiments, the p53 mutation is a K132 mutation. In certain embodiments, the p53 mutation is a K132N mutation. In certain embodiments, the p53 mutation is an R337 mutation. In certain embodiments, the p53 mutation is an R337L mutation. In certain embodiments, the p53 mutation is a W146 mutation. In certain embodiments, the p53 mutation is an S261 mutation. In certain embodiments, the p53 mutation is an S261T mutation. In certain embodiments, the p53 mutation is an E286 mutation. In certain embodiments, the p53 mutation is an E286K mutation. In certain embodiments, the p53 mutation is an R175 mutation. In certain embodiments, the p53 mutation is an R175H mutation. In certain embodiments, the p53 mutation is an E258 mutation. In certain embodiments, the p53 mutation is an E258K mutation. In certain embodiments, the p53 mutation is an a161 mutation. In certain embodiments, the p53 mutation is an a161T mutation.
In certain embodiments, the multiple myeloma has a homozygous deletion of p53. In certain embodiments, the multiple myeloma has a homozygous deletion of wild type p53. In certain embodiments, the multiple myeloma has wild-type p53.
In certain embodiments, multiple myeloma exhibits activation of one or more oncogenic drivers. In certain embodiments, the one or more oncogenic drivers are selected from the group consisting of: C-MAF, MAFB, FGFR, MMset, cyclin D1 and cyclin D. In certain embodiments, multiple myeloma exhibits activation of C-MAF. In certain embodiments, multiple myeloma exhibits activation of MAFB. In certain embodiments, multiple myeloma exhibits activation of FGFR3 and MMset. In certain embodiments, multiple myeloma exhibits activation of C-MAF, FGFR3, and MMset. In certain embodiments, the multiple myeloma exhibits activation of cyclin D1. In certain embodiments, multiple myeloma exhibits activation of MAFB and cyclin D1. In certain embodiments, multiple myeloma exhibits activation of cyclin D.
In certain embodiments, multiple myeloma has one or more chromosomal translocations. In certain embodiments, the chromosomal translocation is t (14; 16). In certain embodiments, the chromosomal translocation is t (14; 20). In certain embodiments, the chromosomal translocation is t (4; 14). In certain embodiments, chromosomal translocations are t (4; 14) and t (14; 16). In certain embodiments, the chromosomal translocation is t (11; 14). In certain embodiments, the chromosomal translocation is t (6; 20). In certain embodiments, the chromosomal translocation is t (20; 22). In certain embodiments, chromosomal translocations are t (6; 20) and t (20; 22). In one embodiment, the chromosomal translocation is t (16; 22). In certain embodiments, chromosomal translocations are t (14; 16) and t (16; 22). In certain embodiments, chromosomal translocations are t (14; 20) and t (11; 14).
In certain embodiments, multiple myeloma has a Q331 p53 mutation, activation of C-MAF, and chromosomal translocation at t (14; 16). In certain embodiments, multiple myeloma has homozygous deletion of p53, activation of C-MAF, and chromosomal translocation at t (14; 16). In certain embodiments, multiple myeloma has a K132N p mutation, activation of MAFB, and chromosomal translocation at t (14; 20). In certain embodiments, multiple myeloma has activation of wild-type p53, FGFR3, and MMset, and chromosomal translocation at t (4; 14). In certain embodiments, multiple myeloma has wild-type p53, activation of C-MAF, and chromosomal translocation at t (14; 16). In certain embodiments, multiple myeloma has homozygous deletion of p53, activation of FGFR3, MMset, and C-MAF, and chromosomal translocations at t (4; 14) and t (14; 16). In certain embodiments, multiple myeloma has homozygous deletion of p53, activation of cyclin D1, and chromosomal translocation at t (11; 14). In certain embodiments, multiple myeloma has a mutation of R337L p, activation of cyclin D1, and chromosomal translocation at t (11; 14). In certain embodiments, multiple myeloma has a W146 p53 mutation, activation of FGFR3 and MMset, and chromosomal translocation at t (4; 14). In certain embodiments, multiple myeloma has a S261T p mutation, activation of MAFB, and chromosomal translocations at t (6; 20) and t (20; 22). In certain embodiments, multiple myeloma has an E286K p mutation, activation of FGFR3 and MMset, and chromosomal translocation at t (4; 14). In certain embodiments, multiple myeloma has a mutation of R175H p, activation of FGFR3 and MMset, and chromosomal translocation at t (4; 14). In certain embodiments, multiple myeloma has a mutation of E258K p, activation of C-MAF, and chromosomal translocations at t (14; 16) and t (16; 22). In certain embodiments, multiple myeloma has activation of wild-type p53, MAFB, and cyclin D1, and chromosomal translocations at t (14; 20) and t (11; 14). In certain embodiments, multiple myeloma has an A161T p mutation, activation of cyclin D, and chromosomal translocation at t (11; 14).
In some embodiments, multiple myeloma is a new diagnostic multiple myeloma suitable for transplantation. In other embodiments, multiple myeloma is a new diagnosis of multiple myeloma that is unsuitable for transplantation.
In some embodiments, the multiple myeloma exhibits early progression (e.g., less than 12 months) following initial treatment. In other embodiments, multiple myeloma exhibits early progression (e.g., less than 12 months) following autologous stem cell transplantation. In another embodiment, the multiple myeloma is refractory to lenalidomide. In another embodiment, the multiple myeloma is refractory to pomalidomide. In some such embodiments, multiple myeloma is predicted to be refractory to pomalidomide (e.g., by molecular characterization). In another embodiment, multiple myeloma is ineffective against 3 or more relapses or treatments and is exposed to, or has dual resistance to, a proteasome inhibitor (e.g., bortezomib, carfilzomib, iferum Sha Zuomi, osprex, or marzomib) and an immunomodulatory compound (e.g., thalidomide, lenalidomide, pomalidomide, ibupine, or awamomi-mine). In other embodiments, multiple myeloma relapses or refractory to 3 or more previous therapies, including, for example, double resistance to CD38 monoclonal antibodies (CD 38 mabs, e.g., up to Lei Tuoyou mAb or itumumab), proteasome inhibitors (e.g., bortezomib, carfilzomib, i Sha Zuomi, or malizomib) and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, ibalylamine, or avaalidomide) or proteasome inhibitors or immunomodulatory compounds and CD38 mabs. In other embodiments, multiple myeloma is triple refractory, e.g., multiple myeloma is refractory to proteasome inhibitors (e.g., bortezomib, carfilzomib, iferum Sha Zuomi, osprex, or marzomib), immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, ibundamine, or awamorinone), and one other active agent, as described herein.
In certain embodiments, a method for treating or controlling relapsed or refractory multiple myeloma in a patient suffering from impaired renal function or symptoms thereof is provided, the method comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
In another embodiment, a method is provided for treating or controlling relapsed or refractory multiple myeloma in a patient suffering from physical weakness, comprising administering to the patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier, to form a composition, wherein the patient suffering from physical weakness is characterized by being unsuitable for induction therapy or intolerance to dexamethasone therapy. In other embodiments, the infirm patient is an elderly person, for example, older than 65 years.
In another embodiment, a method for treating or controlling four-wire relapsed or refractory multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
In another embodiment, a method for treating or controlling newly diagnosed, non-suitable for transplantation multiple myeloma is provided, comprising administering to a patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
In another embodiment, a method for treating or controlling newly diagnosed, non-suitable multiple myeloma for transplantation is provided comprising administering to a patient an effective amount of a compound of formula I or a pharmaceutically acceptable salt, isotopic analog or prodrug thereof, optionally in a pharmaceutically acceptable carrier, to form a composition as another therapy or maintenance therapy after transplantation.
In another embodiment, a method for treating or controlling a high risk of recurrence or refractory multiple myeloma for one, two, or three previous treatments is provided, comprising administering to a patient an effective amount of a compound of formula I, or a pharmaceutically acceptable salt, isotopic analog, or prodrug thereof, optionally in a pharmaceutically acceptable carrier to form a composition.
In some embodiments, a patient to be treated with one of the compounds described herein is not treated with multiple myeloma therapy prior to administration. In some embodiments, a patient to be treated with one of the compounds described herein has been treated with multiple myeloma therapy prior to administration. In some embodiments, a patient to be treated with one of the compounds described herein has developed resistance to multiple myeloma therapy. In some embodiments, a patient to be treated with one of the compounds described herein has developed resistance to one, two, or three multiple myeloma therapies, wherein the therapies are selected from the group consisting of CD38 antibodies (CD 38 mAB, e.g., dasatin Lei Tuoyou or isatuximab), proteasome inhibitors (e.g., bortezomib, carfilzomib, i Sha Zuomi, or marlazomib), and immunomodulatory compounds (e.g., thalidomide, lenalidomide, pomalidomide, ibupitamine, or availamide).
The compounds described herein are useful for treating patients regardless of their age. In some embodiments, the individual is 18 years old or older. In other embodiments, the individual is over 18 years old, 25 years old, 35 years old, 40 years old, 45 years old, 50 years old, 55 years old, 60 years old, 65 years old, or 70 years old. In other embodiments, the patient is less than 65 years old. In other embodiments, the patient is over 65 years old. In certain embodiments, the patient is an elderly multiple myeloma patient, e.g., a patient older than 65 years. In certain embodiments, the patient is an elderly multiple myeloma patient, e.g., a patient older than 75 years old.
It has been reported that certain proteins with β -hairpin turns containing glycine at strategic positions (— g-cycloprotein "or-g-cyclophilin-solving stator") act as-structural-lowering-solving stators of the hydroxycerebroside when it also binds to the thalidomide-like molecule (IMiD) novel substrate protein. Such proteins containing a-g-loop degradation determinant "typically include small anti-parallel β -sheets forming β -hairpins with α -turns, with a geometric arrangement of three backbone hydrogen bond acceptors at the vertices of the turns (positions i, i+1 and i+2), with glycine residues at the critical positions (i+3) (see, e.g., matyskiela et al, A novel cereblon modulator recruits GSPT to the CRL4-CRBN ubiquitin ligand 535,252-257 (2016); sievers et al, defining the human C H2 zinc finger degrome targeted by thalidomide analogs through CRBN. Science 362, eaat0572 (2018)). These g-ring down solution stators have been identified in a number of proteins including, but not limited to Sal-like 4 (SALL 4), GSPT1, IKFZ3 and Ckla, ZFP91, ZNF93, and the like.
In some embodiments, the tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, can be administered to a host in an amount effective to degrade a protein containing g-RING down-resolution stator, wherein the protein is selected from the group consisting of protein kinase, a zinc finger protein containing C2H2, a protein containing RNA recognition motif, a protein containing zinc beta band, a protein containing beta-propeller, a protein containing P-cyclop NTP enzyme, a protein containing a novel gene of Real Interest (RING) -finger domain, a protein containing SRC homology 3 (SH 3) -domain, a protein containing immunoglobulin E-group domain, a protein containing Tudor-domain, a protein containing zinc finger FYVE/PHD-domain, a protein containing Ig-like domain, a protein containing ubiquitin-like domain, a protein containing concanavalin-like domain, a protein containing C1 domain, a protein containing Plastrin Homology (PH) domain, a protein containing OB-fold domain, a protein containing immunoglobulin E-domain, a protein containing ssman-fold domain containing protein, and a protein containing NAD-fold domain containing protein containing a NAD-like domain. In some embodiments, protein kinases, zinc finger proteins containing C2H2, proteins containing RNA recognition motifs, proteins containing zinc beta-bands, proteins containing beta-propellers, proteins containing P-RING NTP enzymes, proteins containing a novel gene of Real Interest (RING) -finger domain, proteins containing Tudor-domain, proteins containing zinc finger FyVE/PHD-type, proteins containing Ig-like domain, proteins containing ubiquitin-like domain, proteins containing concanavalin-like domain, proteins containing C1 domain, proteins containing Pleckstrin Homology (PH) domain, proteins containing OB-fold domain, proteins containing NAD Prossman-fold domain, proteins containing actin-like ATPase domain, or proteins containing spiral-turn-helix (HTH) -domain are overexpressed or contain a gain-of-function mutation.
In some embodiments, the degradation determinant is stabilized by internal hydrogen bonds from the ASX motif and the ST motif.
In some embodiments, the tricyclic heterobifunctional compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, can be administered to a host in an amount effective to degrade a protein having a-G-ring degradation resolution stator "comprising a [ D/N ] XX [ S/T ] G motif (SEQ ID NO: 1), wherein d=aspartic acid, n=asparagine, X can be any amino acid residue, s=serine, t=threonine, and g=glycine. In certain embodiments, the protein comprising the-G-ring down-solving stator "comprises the amino acid sequence DXXSG (SEQ ID NO: 2), wherein d=aspartic acid, X can be any amino acid residue, s=serine, and g=glycine. In another embodiment, the protein containing the-G-ring down resolver "comprises the amino acid sequence nxfsg (SEQ ID NO: 3), where n=asparagine, X can be any amino acid residue, s=serine, and g=glycine. In another embodiment, the protein containing the-G-ring down resolver "comprises the amino acid sequence DXXTG (SEQ ID NO: 4), wherein d=aspartic acid, X can be any amino acid residue, t=threonine, and g=glycine. In another embodiment, the protein containing the-G-ring down resolver "comprises the amino acid sequence nxttg (SEQ ID NO: 5), where n=asparagine, X can be any amino acid residue, t=threonine, and g=glycine. In some embodiments, the protein containing the-G-ring down resolver "comprises the amino acid sequence CXXCG (SEQ ID NO: 6), wherein c=cysteine, X can be any amino acid residue, and g=glycine. In certain embodiments, the protein containing the-G-ring down resolver "comprises the amino acid sequence nxng (SEQ ID NO: 7), where n=asparagine, X can be any amino acid residue, and g=glycine.
In some embodiments, the tricyclic heterobifunctional compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, can be administered to a host in an amount effective to degrade a protein having a C2H2 zinc finger domain containing a-g-ring degradation determinant. In some embodiments, the zinc finger domain has the consensus sequence C-X-C-G (SEQ ID NO: 8), wherein c=cysteine, x=any amino acid, and g=glycine. In another embodiment, the protein having a zinc finger domain has the consensus sequence Q-C-X-C-G (SEQ ID NO: 9), wherein c=cysteine, x=any amino acid, g=glycine, q=glutamine. In another embodiment, the zinc finger domain has the consensus sequence Q-C-X2-C-G-X3-F-X5-L-X2-H-X3-H (SEQ ID NO: 10), wherein c=cysteine, x=any amino acid, g=glycine, q=glutamine, f=phenylalanine, l=leucine, and h=histidine. In some embodiments, the C2H2 zinc finger domain contains X2-C-X2-CG-X2-C-X5 (SEQ ID NO: 11), wherein c=cysteine, x=any amino acid, and g=glycine. In some embodiments, a protein comprising a C2H2 zinc finger domain is overexpressed. In some embodiments, expression of the C2H 2-containing zinc finger protein is associated with a disease or disorder, including, but not limited to, cancer.
For example, a compound of the invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, is administered to a host to degrade zinc finger proteins, atypical E3 ubiquitin ligase (ZFP 91). Zinc finger proteins, atypical E3 ubiquitin ligases contain Cys2-His2 zinc fingers and protect tumor cells from survival and confer chemoresistance by destabilization with the fork cassette A1 (FOXA 1) (see, e.g., tang, et al The ubiquitinase ZFP91 promotes tumor cell survival and confers chemoresistance through FOXA Destabilization, carcinogenies, col.41 (1), jan. 2020). It is believed that zinc finger proteins, atypical E3 ubiquitin ligases function through non-classical NF-. Kappa.B pathway modulation, and that their overexpression leads to increased activation of NF-. Kappa.B signaling pathway, have been implicated in a number of cancers including gastric, breast, colon, renal, ovarian, pancreatic, gastric, prostate, sarcoma and melanoma (see, e.g., paschke, ZFP91 zinc finger protein expression pattern in normal tissues and cancer Oncol Lett.2019; mar;17 (3): 3599-3606). In certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are useful for degrading zinc finger proteins, atypical E3 ubiquitin ligases, useful for treating cancers, including but not limited to gastric, breast, colon, lung, kidney, ovarian, pancreatic, gastric, prostate, sarcoma, and melanoma. In certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are used to degrade zinc finger proteins, atypical E3 ubiquitin ligase to treat sarcoma, melanoma, or gastric cancer.
In another embodiment, a compound of the invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, is administered to a host to degrade zinc finger protein 276 (ZFP 276).
In yet another embodiment, a compound of the invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, is administered to a host to degrade zinc finger protein 653 (ZFP 653). Zinc finger protein 653 can act as a more general repressor of transcription by competing with GRIP1 and other p160 coactivators for binding to SF1 (see, e.g., borud et al, cloning and characterization of a novel zinc finger protein that modulates the transcriptional activity of nuclear acceptors. Molecular. Endocr.17:2303-2319, 2003).
As other examples, a compound of the invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, is administered to a host in an amount effective to degrade zinc finger protein 692 (ZFP 692). Zinc finger protein 692, also known as AICAR Response Element Binding Protein (AREBP), contains a Cys2-His2 zinc finger and is believed to be a key regulator of hepatic glucose production regulated by AMPK in vivo (see Shirai et al, AICAR Response Element Binding Protein (AREBP), a key modulator of hepatic glucose production regulated by AMPK in vivo. Biochem Biophys Res Commun.2011Oct 22;414 (2): 287-91). Over-expression is associated with promotion of colon adenocarcinoma and metastasis by activation of the PI3K/AKT pathway (see, e.g., xing et al, zinc finger protein 692promotes colon adenocarcinoma cell growth and metastasis by activating the PI3K/AKT pathway. Int J Oncol.2019May;54 (5): 1691-1703), and development of metastasis in lung adenocarcinoma and lung cancer. Knocking down zinc finger protein 692 expression by short interfering RNA reduces cell invasion and increases apoptosis in lung cancer cells and inhibits lung cancer tumor growth in xenograft models (see, e.g., zhang et al, ZNF692 promotes proliferation and cell mobility in lung adenocarcinoma. Biochem Biophys Res commun.2017sep 2;490 (4): 1189-1196). Thus, in certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are used to degrade zinc finger protein 692 for the treatment of lung cancer or colon cancer, including lung adenocarcinoma or lung cancer or colon adenocarcinoma.
The tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, may also be administered to a host in an amount effective to degrade zinc finger protein 827 (ZFP 827). Zinc finger protein 827 is a zinc finger protein that modulates the alternative elongation (ALT) pathway of telomeres by binding to nuclear receptors and recruiting nucleosome remodeling and histone deacetylation (NURD) complexes to the telomeres to induce homologous recombination (see, e.g., conomos, D., reddel, R.R., pickett, H.A. NuRD-ZNF827 recruitment to telomeres creates a molecular scaffold for homologous recombination. Nature structure. Molecular. Biol.21:760-770, 2014). Zinc finger protein 827 is associated with ALT-associated promyelocytic leukemia (PML) nucleosomes (APB) and other telomere aberrations. Thus, in certain embodiments, a compound of the invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, is used to degrade ZNF827 in ALT-related disorders including, but not limited to, ALT-positive promyelocytic leukemia, osteosarcoma, adrenal/PNS neuroblastoma, breast cancer, glioblastoma, colorectal cancer, pancreatic neuroendocrine tumor (NET), neuroendocrine tumor, colorectal cancer, liver cancer, soft tissue cancer, including leiomyosarcoma, malignant fibrous histiocytoma, liposarcoma, gastric cancer, testicular cancer, and thyroid cancer.
In other embodiments, the tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are administered to a host in an amount effective to degrade the E4F transcription factor 1 protein (E4F 1). E4F transcription factor 1 is believed to function as a ubiquitin ligase for p53 and is a key post-translational regulator of p53, which plays an important role in cell life or death decisions controlled by p53 (see, e.g., lecam et al, the E4F protein is required for mitotic progression during embryonic cell cycles. Molecular. Cell. Biol.24:6467-6475, 2004). E4F1 overexpression is associated with the development of myeloid leukemia cells (see, e.g., hatachi et al, E4F1 deficiency results in oxidative stress-mediated cell death of leukemic cells. J Exp Med. 201djul 4;208 (7): 1403-1417). Thus, in certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are useful for degrading E4F transcription factor 1 to treat myelogenous leukemia, including but not limited to Acute Myelogenous Leukemia (AML), undifferentiated AML, myeloblastic leukemia with minimal cellular maturation, myeloblastic leukemia with cellular maturation, promyelocytic leukemia, myelomonocytic leukemia with eosinophilia, monocytic leukemia, erythroleukemia, megakaryoblastic leukemia, chronic Myelogenous Leukemia (CML), juvenile myelomonocytic leukemia (JMML), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasms, including, for example, polycythemia Vera (PV), idiopathic thrombocythemia (ET), myelometaplastic myelofibrosis (MMM), eosinophilic syndrome (HES), systemic Mastocytosis (SMCD), myelofibrosis, and primary myelofibrosis. E4F1 expression is also essential for survival in p 53-deficient cancer cells (see, e.g., rodier et al The Transcription Factor E F1 Coordinates CHK1-Dependent Checkpoint and Mitochondrial functions. Cell Reports Volume 11, ISSUE 2, P220-233,April 14,2015). Thus, in certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are useful for degrading E4F transcription factor 1 to treat p 53-deficiency related disorders including, but not limited to, ovarian cancer, small cell lung cancer, pancreatic cancer, head and neck squamous cell carcinoma, and triple negative breast cancer.
In another aspect, the tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are administered to a host in an amount effective to degrade zinc finger protein 517 (ZFP 517). Zinc finger protein 517 has been identified as an oncogenic driver in adrenocortical carcinoma (ACC) (see, e.g., rahane et al, establishing a human adrenocortical carcinoma (ACC) -specific gene mutation signature.cancer genet.2019; 230:1-12). Thus, in certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are used to degrade zinc finger protein 517 to treat adrenocortical carcinoma.
In another aspect, the tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are administered to a host in an amount effective to degrade zinc finger protein 582 (ZFP 582). Zinc finger protein 582 is believed to be involved in n DNA damage response, proliferation, cell cycle control and neoplastic transformation, most notably cervical, esophageal and colorectal cancers (see, e.g., huang et al, methylomic analysis identifies frequent DNA methylation of zinc finger protein (ZNF 582) in consumer neoplasms.PLoS One 7:e41060,2012; tang et al, aberrant DNA methylation ofPAXL, SOX1 and ZNF582 genes as potential biomarkers for esophageal squamous cell caryoma.biomedicine & Pharmacotherapy Volume 120,December 2019,109488;Harada et al, analysis of DNA Methylation in Bowel Lavage Fluid for Detection of Colorectal cancer.cancer Prev Res;7 (10); 1002-10; 2014). Thus, in certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are used to degrade zinc finger protein 582 to treat cancers, including but not limited to cervical cancer, including cervical adenocarcinoma; esophageal cancer, including squamous cell carcinoma and adenocarcinoma; colorectal cancer.
In another embodiment, the tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are administered to a host in an amount effective to degrade zinc finger protein 654 (ZFP 654).
Alternatively, the tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition described herein, are administered to a host in an amount effective to degrade zinc finger protein 787 (ZFP 787).
The tricyclic compounds of the present invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, may be administered to a host in an amount effective to degrade proteins hypermethylated in cancer 1 (HIC 1). The hypermethylated protein in cancer 1 contains an N-terminal BTB/POZ protein-protein interaction domain and a 5 kruppel-like C2H2 zinc finger motif in its C-terminal half (see, e.g., deltour et al, the carboxy-terminal end of The candidate tumor suppressor gene HIC-1is phylogenetically conserved.Biochim.Biophys.Acta 1443:230-232,1998). Expression of hypermethylation in the cancer 1 protein gene disorder Miller-Dieker syndrome (see, e.g., grimm et al, isolation and embryonic expression of the novel mouse gene Hicl, the homologue of HIC1, acandidate gene for the Miller-Dieker syndrome. Hum. Molecular. Genet.8:697-710, 1999).
The tricyclic compounds of the present invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are administered to a host in an amount effective to degrade hypermethylated (HIC 2) proteins in cancer 2.
The tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, may be administered to a host in an amount effective to degrade GDNF-inducible zinc finger protein 1 (GZF 1). GDNF-inducible zinc finger protein 1is a transcriptional regulator that binds to the 12-bp GZF1 response element (GRE) and inhibits gene transcription (see, e.g., morinaga et al, GDNF-inducible zinc finger protein 1is a sequence-specific transcriptional repressor that binds to the HOXA10 gene regulatory regions. Nucleic Acids Res.33:4191-4201, 2005).
Alternatively, for example, the tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, may be administered to a host in an amount effective to degrade the Odd-skip-related 1 (OSR 1) protein. The Odd-clamped related 1 protein contains 3C 2H 2-type zinc fingers, one tyrosine phosphorylation site, and several putative PXXP SH3 binding motifs (see, e.g., katoh, M.molecular cloning and characterization of OSR1 on human chromosome p24.Int. J. Molecular Med.10:221-225,2002).
In another aspect, the tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are administered to a host in an amount effective to degrade the Odd skip-associated 2 (OSR 2) protein.
In yet another embodiment, a selected tricyclic compound of the invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, can be administered to a host in an amount effective to degrade SAL-like 4 (SALL 4) protein. SAL-like 4 proteins have 3 SAL-type C2H2 double zinc finger domains, the second of which has a single C2H2 zinc finger linked at its C-terminus, and an N-terminal C2HC zinc finger motif typical for vertebrate SAL-like proteins. SAL-like 4 protein mutations are associated with the development of Duane-radial syndrome (see, e.g., borozdin et al, SALL4 deletions are a common cause of Okihiro and acro-renal-ocular syndromes and confirm haploinsufficiency as the pathogenic mechenism. J. Med. Genet.41:el 13,2004). SAL-like 4 protein overexpression is associated with promotion, growth, and metastasis of a variety of cancers, including lung cancer, gastric cancer, liver cancer, renal cancer, myelodysplastic syndrome, germ cell-sex cord interstitial tumors (including asexual cell tumors, yolk sac tumors, and choriocarcinomas), leukemia, and the like. Thus, in certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are useful for degrading SAL-like 4 proteins to treat cancers, including, but not limited to, gastric cancer, liver cancer, renal cancer, myelodysplastic syndrome, germ cell-sex cord interstitial tumors (including asexual cell tumors, yolk sac tumors, and choriocarcinomas), leukemia, and the like.
The selected tricyclic compounds of the present invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, may also be administered to a host in an amount effective to degrade B cell lymphoma6 (BCL 6) protein. B cell lymphoma6 contains an autonomous trans-repressor domain and 2 non-contiguous regions, including the POZ motif, that mediate the greatest trans-repressing activity. Translocation of B-cell lymphoma6 gene translocation is associated with the development of myeloproliferative diseases such as non-hodgkin's lymphoma. The over-expression of B-cell lymphoma6 prevents the increase of reactive oxygen species and inhibits chemotherapy-induced apoptosis in Cancer cells (see, e.g., tahara et al Overexpression of B-cell lymphoma6alters gene expression profile in a myeloma cell line and is associated with decreased DNA damage response. Cancer Sci.2017Aug;108 (8): 1556-1564; cardeas et al The expanding role of the BCL6 oncoprotein as a Cancer therapeutic target. Clin Cancer Res.2017Feb 15;23 (4): 885-893). Thus, in certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are used to degrade B-cell lymphoma6 for the treatment of cancers, including but not limited to hematological or solid tumors, such as but not limited to B-cell leukemia or lymphomas, such as but not limited to diffuse large B-cell lymphoma (DLBCL) and ABC-DLBCL subtypes, B-acute lymphoblastic leukemia, chronic myelogenous leukemia, breast cancer, and non-small cell lung cancer.
Furthermore, the selected tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are administered to a host in an amount effective to degrade B cell lymphoma 6B (BCL 6B) protein. The B cell lymphoma 6B protein contains an N-terminal POZ domain and 5C-terminal zinc finger motifs and is believed to act as a transcriptional repressor (see, e.g., okabe et al, BAZF, a novel Bcl6 homolog, functions as a transcriptional repressor. Molecular. Cell. Biol.18:4235-4244, 1998). Overexpression of the B cell lymphoma 6B protein is associated with the development of germ cell tumors (Ishii et al, FGF2 mediates mouse spermatogonial stem cell self-renewal via upregulation of Etv5and Bcl6bthrough MAP2K1 activation. Development 139,1734-1743 (2012)). Thus, in certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are used to degrade B cell lymphoma 6B for the treatment of cancers, including but not limited to germ cell tumors, including apomictic and seminoma, teratomas, yolk sac tumors, and choriocarcinomas.
Alternatively, the selected tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, may be administered to a host in an amount effective to degrade early growth response 1 (EGR 1) proteins. Early growth response 1 proteins directly control transforming growth factor-beta-1 gene expression and have been shown to be involved in the proliferation and survival of prostate cancer cells as well as glioma cells by modulating several target genes, including cyclin D2 (CCND 2), p19 (Ink 4D) and Fas (see, e.g., virol et al, ergl promotes growth and survival of prostate cancer cells: identification of novel Egrl target genes. J. Biol. Chem.278:11802-11810,2003; chen et al, inhibition of EGR1inhibits glioma proliferation by targeting CCND. Precursor. Journal of Experimental & Clinical Cancer Research Volume 36,Article number:186 (2017)). One mechanism by which Egr1 confers resistance to apoptotic signals is the ability of Egr1 to inhibit Fas expression, resulting in insensitivity to FasL. Thus, in certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are used to degrade early growth response 1 proteins to treat cancers, including but not limited to prostate cancer or gliomas, including but not limited to hairy cell astrocytomas, diffuse astrocytomas, anaplastic astrocytomas, glioblastoma multiforme.
In another aspect, a selected tricyclic compound of the invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, may be administered to a host in an amount effective to degrade early growth response 4 (EGR 4) protein. Early growth response 4 proteins contain 3 zinc fingers of the C2/H2 subtype near the carboxy terminus (see, e.g., crosby et al, nereal-specific expression, genomic structure, and chromosomal localization of the gene encoding the zinc-finger transcription factor NGFI-C.Proc.Nat. Acad.Sci.89:4739-4743, 1992). Overexpression of early growth response 4 protein has been associated with the development of cholangiocarcinoma (see, e.g., gong et al Gramicidin inhibits cholangiocarcinoma cell growth by suppressing egr4. Artifical Cells, nanomedicine, and Biotechnology,48:1,53-59 (2019)). Thus, in certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are used to degrade early growth response 4 protein to treat cancer, including but not limited to cholangiocarcinoma.
In certain aspects, a selected tricyclic compound of the invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, can be administered to a host in an amount effective to degrade Sal-like 1 (SALL 1) protein.
In one embodiment, a selected tricyclic compound of the invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, can be administered to a host in an amount effective to degrade Sal-like 3 (SALL 3) protein. SALL3 protein contains 4 Double Zinc Finger (DZF) domains, each containing sequences identical or closely related to SAL cassettes, with a characteristic extension of 8 amino acids (stretch) in the second zinc finger motif.
In yet another embodiment, a selected tricyclic compound of the invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, can be administered to a host in an amount effective to degrade tumor protein p63 (TP 63). Tumor protein p63 overexpression is associated with lung cancer progression and poor prognosis, radiation resistance in oral and head and neck cancer, squamous cell carcinoma of the skin (see, e.g., mass et al, significance of p63 amplification and overexpression in lung cancer development and prognosis. Cancer Res.2003Nov1;63 (21): 7113-21; moergel et al, overexpression of p63 is associated with radiation resistance and prognosis in oral squamous cell carcinoma. Oral Oncol.2010Sep;46 (9): 667-71). Thus, in certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are used to degrade tumor protein p63 to treat cancers, including, but not limited to, non-small cell lung cancer, head and neck cancer, and cutaneous squamous cell carcinoma.
In yet another embodiment, the selected tricyclic compounds of the present invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, may be administered to a host in an amount effective to degrade widely spaced zinc finger (WIZ) proteins.
The selected tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, can also be administered to a host in an amount effective to degrade zinc finger and BTB domain containing protein 7A (ZBTB 7A). Protein 7A expression, which contains zinc finger and BTB domains, is associated with a number of cancers, including prostate cancer, non-small cell lung cancer, bladder cancer, breast cancer, prostate cancer, ovarian cancer, oral squamous cell carcinoma, and hepatocellular carcinoma (see, e.g., han et al, ZBTB7AMediates the Transcriptional Repression Activity of the Androgen Receptor in Prostate cancer Res 2019;79:5260-71; molloy et al, ZBTB7A governs estrogen receptor alpha expression in breast cancer. Journal of Molecular Cell Biology, volume 10, stage 4, august 2018, pages 273-284). Thus, in certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are useful for degrading protein 7A containing zinc finger and BTB domains, for treating cancers, including, but not limited to, prostate cancer, non-small cell lung cancer, breast cancer, oral squamous cell carcinoma, prostate cancer, ovarian cancer, glioma, bladder cancer, and hepatocellular carcinoma.
In other aspects, a selected tricyclic compound of the invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, can be administered to a host in an amount effective to degrade protein 7B (ZBTB 7B) containing zinc finger and BTB domains. Protein 7B expression, which contains zinc finger and BTB domains, is associated with breast cancer, prostate cancer, urothelial cancer, cervical cancer and colorectal cancer. Thus, in certain embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are useful for degrading protein 7B containing zinc finger and BTB domains, for treating cancers, including, but not limited to, breast cancer, prostate cancer, urothelial cancer, cervical cancer, and colorectal cancer.
The selected tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, can be administered to a host in an amount effective to degrade casein kinase I, αi (ck1α or CK1- α). CK 1-alpha is a bifunctional modulator of NF-kappa-B (see, e.g., bidere et al, casein kinase 1-alpha governs antigen-receiver-induced NF-kappa-Bactivation and human lymphoma cell survivinal. Nature 458:92-96,2009). CK1- α is dynamically associated with CBM complexes on T cell receptors to participate in cytokine production and lymphocyte proliferation. However, CK 1-alpha kinase activity has an opposite effect by subsequently promoting phosphorylation and inactivation of CARMA 1. Thus, CK1- α has a dual-gating "function, which first promotes and then terminates receptor-induced NF- κ -B. ABC DLBCL cells require CK1- α for constitutive NF- κ -B activity, indicating that CK1- α functions as a conditionally essential malignant gene. CK1- α expression and myelodysplastic diseases accompanied by depletion of 5q (del (5 q) MDS (see, e.g., kronke, et al, lenalidomide induces ubiquitination and degradation of CKl-alpha in del (5 q) MDS. Nature 523:183-188,2015), colorectal cancer, breast cancer, leukemia, multiple myeloma, lung cancer, diffuse large B-cell lymphoma, non-small cell lung cancer, pancreatic cancer, and the like (see, e.g., richter, CKla overexpression correlates with poor survival in colorectal cancer. BMC cancer.2018;18:140; jiang et al, casein kinase la: biological mechanisms and theranostic potential cell Commun Signal.2018; 16:23), thus, in some embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are useful for degrading Casein kinase I, αI for the treatment of cancers, including but not limited to colorectal cancer, breast cancer, leukemia, multiple myeloma, lung cancer, diffuse large B cell lymphoma, non-small cell lung cancer, pancreatic cancer, myelodysplastic syndrome, including but not limited to 5 q-syndrome, refractory cytopenia with monoclinic dysplasia, refractory anemia, refractory neutropenia and refractory thrombocytopenia, refractory anemia with annular iron young cells, refractory Cytopenia (RCMD) with multiple dysplasias, refractory anemia (REAB) I and II with embryonic cells, transformation of refractory anemia (CMMB), refractory myelodysplastic (CMML), and myelodysplastic (myelodysplastic) classification Dysfunctional cytopenia in childhood (childhood dysplasia).
The selected tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, may also be administered to a host in an amount effective to degrade family 83 member H (FAM 83H) having sequence similarity. FAM83H is believed to be involved in the progression of human cancers along with tumor-associated molecules such as MYC and β -catenin, and overexpression is associated with lung cancer, breast cancer, colon cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, esophageal cancer, glioma, hepatocellular carcinoma, thyroid cancer, renal cell carcinoma, osteosarcoma, and gastric cancer (see, e.g., kim et al, FAM83H is involved in stabilization of P-catenin and progression of ossearcom. Journal of Experimental & Clinical Cancer Research volume 38,Article number:267 (2019)). Thus, in some embodiments, a compound of the invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, is used to degrade FAM83H to treat cancers, including but not limited to lung cancer, breast cancer, colon cancer, liver cancer, ovarian cancer, pancreatic cancer, prostate cancer, esophageal cancer, glioma, thyroid cancer, liver cancer (including but not limited to hepatocellular carcinoma), renal cell carcinoma, osteosarcoma, and gastric cancer.
Alternatively, the selected tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, can be administered to a host in an amount effective to degrade zinc finger and BTB domain containing protein 16 (ZBTB 16). Overexpression and translocation of ZBTB16 has been associated with the development of various cancers of the blood system, including acute promyelocytic leukemia (see, e.g., zhang et al, genomic sequence, structural organization, molecular evolution, and aberrant rearrangement of promyelocytic leukemia zinc finger gene. Proc. Nat. Acad. Sci.96:11422-11427,1999). Thus, in some embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are used to degrade ZBTB16 to treat cancers, including but not limited to hematological cancers, including but not limited to leukemia or lymphomas, including but not limited to acute promyelocytic leukemia, acute lymphoblastic leukemia, adult T cell lymphoma/ATL, and Burkitt lymphoma.
In an alternative embodiment, the selected tricyclic compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, can be administered to a host in an amount effective to degrade AT interaction domain-rich protein 2 (ARID 2). ARID2 is a subunit of the PBAF chromatin remodeling complex that promotes ligand-dependent transcriptional activation of nuclear receptors (see, e.g., yan et al, PBAF chromain-remodeling complex requires a novel specificity subunit, BAF200, to regulate expression of selective interferon-responsive genes. Genes Dev.19:1662-1667, 2005).
In another aspect, a selected tricyclic compound of the invention, or a pharmaceutically acceptable salt thereof, optionally in a pharmaceutical composition as described herein, can be administered to a host in an amount effective to degrade polybrominated related BAF (PBAF). Mutations in PBAF are associated with the development of synovial sarcoma and multiple myeloma (see, e.g., alfert et al, the BAF complex in development and disease. Epigenetics & chromain volume 12,Article number:19 (2019)). Thus, in some embodiments, the compounds of the invention, or pharmaceutically acceptable salts thereof, optionally in a pharmaceutical composition as described herein, are used to degrade PBAF to treat cancers, including but not limited to synovial sarcoma and multiple myeloma.
In other embodiments, the selected tricyclic compounds of the invention are capable of binding a number of new substrates to produce a-multi-pharmacological "form when administered after binding to a hydroxycycloglycoside ester and forming a newly deformed surface. For example, tricyclic compounds may bind and degrade IRAK4, IKZF1 and/or IKZF3 and/or Aiolos. In other examples, the tricyclic compound is capable of degrading two or more proteins named above or herein upon administration, such as SALL4 and IKZF1/3 or IKZF2/4.
In certain embodiments, the tricyclic compounds of the invention are at least about 1.5, 2, 3, 5, or even 10-fold selective for the in vitro degradation of IKZF2 and/or IKZF4 over IKZF1 and/or IKZF3 in a standard HiBiT bioluminescence assay. The HiBiT assay is a well known assay that has been fully described in the literature.
VI combination therapy
The selected compounds of formula I, or pharmaceutically acceptable salts thereof, may be used alone or in combination in an effective amount to treat a patient as further described herein.
The disclosed compounds described herein may be used alone or in combination with another compound or another bioactive agent or a second therapeutic agent of the present invention in an effective amount to treat a patient, such as a human, suffering from a disorder including, but not limited to, those described herein.
The term "bioactive agent" is used to describe an agent that is not a compound selected according to the present invention that may be combined or used interchangeably with a compound of the present invention to achieve a desired therapeutic result. In certain embodiments, the compounds and bioactive agents of the present invention are administered in such a way that they have in vivo activity over overlapping time periods, e.g., cmax, tmax, AUC or other pharmacokinetic parameters with overlapping time periods. In another embodiment, the compounds and bioactive agents of the present invention are administered to a patient in need thereof, which do not have overlapping pharmacokinetic parameters, however, one has a therapeutic effect on the therapeutic efficacy of the other.
In one aspect of this embodiment, the bioactive agent is an immunomodulatory agent including, but not limited to, checkpoint inhibitors, including, by way of non-limiting example, PD-1 inhibitors, PD-L2 inhibitors, CTLA-4 inhibitors, LAG-3 inhibitors, TIM-3 inhibitors, V-domain Ig inhibitor of T-cell activation (VISTA) inhibitors, small molecules, peptides, nucleotides, or other inhibitors. In certain aspects, the immunomodulator is an antibody, such as a monoclonal antibody.
PD-1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-1 receptor, thereby inhibiting immunosuppression, include, for example, nivolumab (Opdivo), pembrolizumab (Keystuda), pituzumab AMP-224 (AstraZeneca and MedImmune), PF-06801591 (Pfizer), MEDI0680 (AstraZeneca), PDR001 (Novartis), REGN2810 (Regeneron), SHR-12-1 (Jiangsu Hengrui Medicine Company andIncyte Corporation), TSR-042 (Tesaro), and the PD-L1/VISTA inhibitor CA-170 (Curis Inc.). PD-L1 inhibitors that block the interaction of PD-1 and PD-L1 by binding to the PD-L1 receptor, thereby inhibiting immunosuppression, include, for example, attirizumab (tecontriq), dulcis You Shan antibody (AstraZeneca and MedImmune), KN035 (Alphamab) and BMS-936559 (Bristol-Myers Squibb). CTLA-4 checkpoint inhibitors that bind CTLA-4 and inhibit immunosuppression include, but are not limited to, ipilimumab, tremelimumab (AstraZeneca and MedImmune), AGEN1884 and AGEN2041 (agalus). LAG-3 checkpoint inhibitors include, but are not limited to, BMS-986016 (Bristol-Myers Squibb), GSK2831781 (GlaxoSmithKline), IMP321 (Prima BioMed), LAG525 (Novartis), and dual PD-1 and LAG-3 inhibitors MGD013 (macrogeneics). An example of a TIM-3 inhibitor is TSR-022 (Tesaro).
In certain embodiments, the checkpoint inhibitor is selected from the group consisting of nivolumab +.Pembrolizumab +.And Pittuzumab/CT-011, MPDL3280A/RG7446; MEDI4736; MSB0010718C; BMS936559, a PDL2/lg fusion protein such as AMP 224, or an inhibitor of B7-H3 (e.g., MGA 271), B7-H4, BTLA, HVEM, TIM3, GAL9, LAG 3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligand, or a combination thereof.
In yet another embodiment, one of the active compounds described herein may be combined or alternatively administered in an effective amount to treat abnormal tissues of the female reproductive system, such as breast, ovarian, endometrial or uterine cancers, with an effective amount of an estrogen inhibitor, including but not limited to a SERM (selective estrogen receptor modulator), a SERD (selective estrogen receptor degradation agent), a complete estrogen receptor degradation agent, or another form of partial or complete estrogen antagonist or agonist. Some antiestrogens, such as raloxifene and tamoxifen, retain some estrogen-like effects, including estrogen-like stimulation of uterine growth and, in some cases, estrogen-like effects during breast cancer progression, which actually stimulates tumor growth. In contrast, fulvestrant, a complete antiestrogen, has no estrogen-like effect on the uterus and is effective in tamoxifen resistant tumors.
Non-limiting anti-estrogenic compounds illustrative examples are provided below: WO 2014/19176 assigned to Astra Zeneca; WO2013/090921, WO 2014/203129, WO 2014/203132 and US2013/0178445 assigned to Olema Pharmaceuticals; U.S. patent nos. 9,078,871, 8,853,423 and 8,703,810; US 2015/0005286, WO 2014/205136 and WO 2014/205138.
Further non-limiting examples of antiestrogenic compounds include: SERMS such as mandipropofoxib, bazedoxifene, bropraestriol, chlorotrientine, clomiphene citrate, cyclofenil, lasofoxifene, olmesafen, raloxifene, tamoxifen, toremifene, and fulvestrant; aromatase inhibitors such as aminoglutethimide, testosterone, anastrozole, exemestane, fadrozole, formestane and letrozole; and anti-gonadotropins such as leuprolide, cetrorelix, allylestrenol, megestrol acetate, cyproterone acetate, dygesterone acetate, dydrogesterone acetate, medroxyprogesterone acetate, megestrol acetate, nomestrol acetate, norethindrone acetate, progesterone, and spironolactone.
Other ligands of estrogens that can be used in accordance with the present invention are described in U.S. Pat. nos. 4,418,068, 5,478,847, 5,393,763 and 5,457,117; WO2011/156518; U.S. patent nos. 8,455,534 and 8,299,112; U.S. patent nos. 9,078,871, 8,853,423, 8,703,810; US 2015/0005286; WO 2014/205138; US2016/0175289; US2015/0258080; WO 2014/191726; WO 2012/084711; WO 2002/01302; WO 2002/004418; WO2002/003992; WO 2002/003991; WO 2002/003990; WO 2002/003989; WO 2002/003988; WO2002/003986; WO 2002/003977; WO 2002/003976; WO 2002/003975; WO 2006/078834; US6821989; US 2002/0128676; US 6777424; US 2002/0016340; US 6326392; US 6756401; US2002/0013327; US 6512002; US 6632834; US 2001/0056099; US 6583170; US 6479535; WO 1999/02020247; US 6005102; EP 0802184; US 5998402; US 5780497; US 5880137; WO 2012/048058 and WO 2007/087684.
In another embodiment, the active compounds described herein may be combined or alternatively administered in an effective amount to treat abnormal tissues of the male reproductive system, such as prostate cancer or testicular cancer, with an effective amount of an androgen (e.g., testosterone) inhibitor, including but not limited to a selective androgen receptor modulator, a selective androgen receptor degradant, a complete androgen receptor degradant, or another form of partial or complete androgen antagonist. In certain embodiments, the prostate cancer or testicular cancer is androgen resistant.
Non-limiting examples of anti-androgenic compounds are provided in WO 2011/156518 and U.S. patent nos. 8,455,534 and 8,299,112. Further non-limiting examples of anti-androgenic compounds include: enzalutamide, apalutamide, cyproterone acetate, megestrol acetate, spironolactone, allylic lactone, drospirenone, ketoconazole, topiluamide, abiraterone acetate and cimetidine.
In certain embodiments, the bioactive agent is an ALK inhibitor. Examples of ALK inhibitors include, but are not limited to, crizotinib, aletinib, ceritinib, TAE684 (NVP-TAE 684), GSK1838705A, AZD3463, ASP3026, PF-06463922, emtrictinib (RXDX-101), and AP26113.
In certain embodiments, the bioactive agent is an EGFR inhibitor. Examples of EGFR inhibitors include erlotinib (Tarceva), gefitinib (Iressa), afatinib (Gilottif), luo Xiti ni (CO-1686), ornitinib (Tagrisso), olitinib (Olia), naquotinib (ASP 8273), nazatinib (EGF 816), PF-06747775 (Pfizer), ecotinib (BPI-2009), lenatinib (HKI-272; PB272); eveltinib (AC 0010), EAI045, taxotinib (TH-4000; PR-610), PF-06459988 (Pfizer), tesevatinib (XL 647; EXEL-7647; KD-019), transtinib, WZ-3146, WZ8040, CNX-2006 and dacatinib (PF-00299804; pfizer).
In certain embodiments, the bioactive agent is a HER-2 inhibitor. Examples of HER-2 inhibitors include trastuzumab, lapatinib, enmetrastuzumab, and pertuzumab.
In certain embodiments, the bioactive agent is a CD20 inhibitor. Examples of CD20 inhibitors include oxuzumab, rituximab, ofatuzumab, tiimumab, tositumomab, and orelizumab (ocrelizumab).
In certain embodiments, the bioactive agent is a JAK3 inhibitor. Examples of JAK3 inhibitors include tofacitinib.
In certain embodiments, the bioactive agent is a BCL-2 inhibitor. Examples of BCL-2 inhibitors include vinatoclan (vennetoclax), ABT-199 (4- [4- [ [2- (4-chlorophenyl) -4, 4-dimethylcyclohex-1-en-1-yl ] methyl ] piperazin-l-yl ] -N- [ [ 3-nitro-4- [ [ (tetrahydro-2H-pyran-4-yl) methyl ] amino ] phenyl ] sulfonyl ] -2- [ (lH-pyrrolo [2,3-b ] pyridin-5-yl) oxy ] benzamide), ABT-737 (4- [4- [ [2- (4-chlorophenyl) phenyl ] methyl ] piperazin-1-yl ] -N- [4- [ [ (2R) -4- (dimethylamino) -1-phenylsulfonyl butan-2-yl ] amino ] -3-nitrophenyl ] sulfonyl benzamide) (navitocrax), ABT-263 ((R) -4- (4- ((4' -chloro-4, 4-dimethyl-3, 4,5, 6-tetrahydro- [ l, l' -biphenyl ] -2-yl) methyl) piperazin-1-yl) -N- ((4- ((4-morpholino-1- (phenylsulfanyl) butan-2-yl) amino) -3 ((trifluoromethyl) sulfonyl) phenyl) sulfonyl) benzamide), GX15-070 (obakla mesylate (obatoclax mesylate), (2Z) -2- [ (5Z) -5- [ (3, 5-dimethyl-lH-pyrrol-2-yl) methylene ] -4-methoxypyrrol-2-ylidene ] indole methanesulfonic acid))), 2-methoxy-antimycin A3, YC137 (4- (4, 9-dioxo-4, 9-dihydronaphtho [2,3-d ] thiazol-2-ylamino) -phenyl ester, pogosin, 2-amino-6-bromo-4- (1-cyano-2-ethoxy-2-oxoethyl) -4H-chromen-3-carboxylic acid ethyl ester, nilotinib-d 3, TW-37 (N- [4- [2- (1, 1-dimethyl-phenyl ] p-henyl ] 2- [ -oxo-2-yl) phenyl ] benzoyl ] indole methanesulfonic acid), 2-methoxy-antimycin A3, YC137 (4- (4, 9-dioxo-2, 3-d ] thiazol-2-ylamino) phenyl ester, pogosin, 2-amino-6-bromo-4- (1-cyano-2-ethoxy-2-oxoethyl) -4H-chromen-3-carboxylic acid ethyl ester, nilotin-3-yl ] 2-yl-carbonyl ] 2-sulfonyl ] 2-methyl-amine HA14-1, AT101, sabutoclax, gambogic acid or G3139 (Oblimersen).
In certain embodiments, the bioactive agent is a kinase inhibitor. In one embodiment, the kinase inhibitor is selected from a phosphoinositide 3-kinase (PI 3K) inhibitor, a Bruton's Tyrosine Kinase (BTK) inhibitor, or a spleen tyrosine kinase (Syk) inhibitor, or a combination thereof.
Examples of PI3 kinase inhibitors include, but are not limited to Wortmannin (Wortmannin), desmethylglimycin, piriflumin, idarubicin (idelalisib), pictilisib, palomid529, ZSTK474, PWT33597, CUDC-907 and AEZS-136, du Weili sibutra (duvelisib), GS-9820, BKM120, GDC-0032 (taseliib) (2- [4- [2- (2-isopropyl-5-methyl-1, 2, 4-triazol-3-yl) -5, 6-dihydroimidazo [1,2-d ] [1,4] benzoxazepin-9-yl ] pyrazol-1-yl ] -2-methylpropanamide), MLN-1117 ((2R) -1-phenoxy-2-butanyl hydrogen (S) -methylphosphonate; or methyl (oxo) { [ (2R) -l-phenoxy-2-butanoyl ] oxy } phosphonium)), BYL-719 ((2S) -N1- [ 4-methyl-5- [2- (2, 2-trifluoro-1, 1-dimethylethyl) -4-pyridinyl ] -2-thiazolyl ] -1, 2-pyrrolidinedicarboxamide), GSK2126458 (2, 4-difluoro-N- {2- (methyloxy) -5- [4- (4-pyridazinyl) -6-quinolinyl ] -3-pyridinyl } benzenesulfonamide) (omiplaisib), TGX-221 ((. + -.) -7-methyl-2- (morpholin-4-yl) -9- (l-phenylaminoethyl) -pyrido [ l,2-a ] -pyrimidin-4-one), GSK2636771 (2-methyl-1- (2-methyl-3- (trifluoromethyl) benzyl) -6-morpholino-lH-benzo [ d ] imidazole-4-carboxylic acid dihydrochloride), KIN-193 ((R) -2- ((l- (7-methyl-2-morpholino-4-oxo-4H-pyrido [1,2-a ] pyrimidin-9-yl) ethyl) amino) benzoic acid), TGR-1202/RP5264, GS-9820 ((S) -l- (4- ((2- (2-aminopyrimidin-5-yl) -7-methyl-4-hydroxyprop-1-one), GS-1101 (5-fluoro-3-phenyl-2 [ S) ] -1- [ 9H-purin-6-ylamino ] -propyl) -3H-quinazolin-4-one), AMG-319, GSK-2269557, SAR245409 (N- (4- (N- (3- ((3, 5-dimethoxyphenyl) amino) quinoxalin-2-yl) sulfamoyl) phenyl) -3-methoxy-4-methylbenzamide), BAY80-6946 (2-amino-N- (7-methoxy-8- (3-morpholinopropoxy) -2, 3-dihydroimidazo [ l,2-c ] quinaz), AS 252424 (5- [ l- [5- (4-fluoro-2-hydroxy-phenyl) -furan-2-yl ] -methyl- (Z) -subunit ] -thiazolidine-2, 4-dione), CZ 24832 (5- (2-amino-8-fluoro- [ l,2,4] triazolo [ l,5-a ] pyridin-6-yl) -N-t-butylpyridine-3-sulfonamide), buparlisib (5- [2, 6-di (4-morpholinyl) -4-pyrimidinyl ] -4- (trifluoromethyl) -2-pyridinamine), GDC-41 (2- (H-indazol) -4- (4-methylsulfonyl) -4-morpholino [ 4-methyl ] 2, 4-thienyl ] piperazino [ l ] -4-methyl- [ -4-sulfonyl ] piperazino [ 3-d ] thiophene ] 3-sulfonyl), GDC-0980 ((S) -1- (4- ((2- (2-aminopyrimidin-5-yl) -7-methyl-4-morpholinothioo [3,2-d ] pyrimidin-6-yl) methyl) piperazin-l-yl) -2-hydroxypropane-l-one (also known as RG 7422)), SF1126 ((8S, 14S, 17S) -14- (carboxymethyl) -8- (3-guanidinopropyl) -17- (hydroxymethyl) -3,6,9,12, 15-pentoxy-1- (4- (4-oxo-8-phenyl-4H-chromen-2-yl) morpholin-4-ium) -2-oxa-7,10,13,16-tetraazaoctadecan-18-oate), PF-05212384 (N- [4- [ [4- (dimethylamino) -1-piperidinyl ] carbonyl ] phenyl ] -N' - [4- (4, 6-di-4-morpholinyl-l, 3, 5-triazin-2-yl) phenyl ] urea) (gedatolib), LY3023414, BEZ235 (2-methyl-2- {4- [ 3-methyl-2-oxo-8- (quinolin-3-yl) -2, 3-dihydro-lH-imidazo [4,5-c ] quinolin-l-yl ] phenyl } propionitrile) (dactylisib), XL-765 (N- (3, 5-dimethoxyphenylamino) quinoxalin-2-yl) sulfamoyl) phenyl) -3-methoxy-4-methylbenzamide) and GSK1059615 (5- [4- (4-pyridinyl) -6-quinolinyl ] methylene ] -2, 4-thiazolidinedione), PX886 ([ (3 aR,6E,9S,9aR,10R,11 aS) -6- [ [ bis (prop-2-enyl) amino ] methylene ] -5-hydroxy-9- (methoxymethyl) -9a,11 a-dimethyl-l, 4, 7-trioxo-2, 3a,9,10, ll-hexahydroindeno [4,5h ] isochromen-10-yl ] acetate (also known AS soloisib)), LY294002, AZD8186, PF-4989216, pilaralisib, GNE-317, PI-3065, PI-103, NU7441 (KU-57788), HS 173, VS-5584 (SB 2343), CZC24832, TG100-115, A66, YM201636, CAY10505, PIK-75, PIK-93, AS-605240, BGT226 (NVP-BGT 226), AZD6482, voxtalisib, alpelisib, IC-87114, TGI100713, CH5132799, PKI-402, copan lisib (BAY 80-6946), XL 147, PIK-90, PIK-293, PIK-294, 3-MA (3-methyladenine), AS-252424, AS-604850, apitolisib (GDC-0980; RG7422).
Examples of BTK inhibitors include ibutenib (also known as PCI-32765) (Imbruvica TM ) (1- [ (3R) -3- [ 4-amino-3- (4-phenoxy-phenyl) pyrazolo [3, 4-d)]Pyrimidin-1-yl]Piperidin-1-yl]Prop-2-en-1-one), dianilinopyrimidine-based inhibitors such as AVL-101 and AVL-291/292 (N- (3- ((5-fluoro-2- ((4- (2-methoxyethoxy) phenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide) (Avila Therapeutics) (see U.S. patent publication No. 2011/01119073, which is incorporated herein in its entirety), dasatinib ([ N- (2-chloro-6-methylphenyl) -2- (6- (4- (2-hydroxyethyl) piperazin-1-yl) -2-methylpyrimidin-4-ylamino) thiazole-5-carboxamide]LFM-A13 (α -cyano- β -hydroxy- β -methyl-N- (2, 5-dibromophenyl) acrylamide), GDC-0834 ([ R-N- (3- (6- (4- (1, 4-dimethyl-3-oxopiperazin-2-yl) phenylamino) -4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl) -2-methylphenyl) -4,5,6, 7-tetrahydrobenzo [ b ]]Thiophene-2-carboxamides]CGI-560 4- (tert-butyl) -N- (3- (8- (phenylamino) imidazo [1, 2-a)]Pyrazin-6-yl) phenyl) benzamide, CGI-1746 (4- (tert-butyl) -N- (2-methyl-3- (4-methyl-6- ((4- (morpholin-4-carbonyl) phenyl) amino) -5-oxo-4, 5-dihydropyrazin-2-yl) phenyl) benzamide), CNX-774 (4- (4- ((4- ((3-acrylamidophenyl) amino) -5-fluoropyrimidin-2-yl) amino) phenoxy) -N-methylpyridinamide), CTA056 (7-benzyl-1- (3- (piperidin-1-yl) propyl) -2- (4- (pyridin-4-yl) phenyl) -1H-imidazo [4, 5-g) ]Quinoxalin-6 (5H) -one), GDC-0834 ((R) -N- (3- (6- ((4- (1, 4-dimethyl-3-oxopiperazin-2-yl) phenyl) amino) -4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl) -2-methylphenyl) -4,5,6, 7-tetrahydrobenzo [ b)]Thiophene-2-carboxamide), GDC-0837 ((R) -N- (3- (6- ((4- (1, 4-dimethyl-3-oxopiperazin-2-yl) phenyl) amino)Phenyl) -4-methyl-5-oxo-4, 5-dihydropyrazin-2-yl) -2-methylphenyl) -4,5,6, 7-tetrahydrobenzo [ b]Thiophene-2-carboxamide), HM-71224, ACP-196, ONO-4059 (Ono Pharmaceuticals), PRT062607 (4- ((3- (2H-1, 2, 3-triazol-2-yl) phenyl) amino) -2- (((1R, 2S) -2-aminocyclohexyl) amino) pyrimidine-5-carboxamide hydrochloride), QL-47 (1- (1-propenylindolin-6-yl) -9- (1-methyl-1H-pyrazol-4-yl) benzo [ H)][1,6]Naphthyridin-2 (1H) -one) and RN486 (6-cyclopropyl-8-fluoro-2- (2-hydroxymethyl-3- { 1-methyl-5- [5- (4-methyl-piperazin-1-yl) -pyridin-2-ylamino)]-6-oxo-1, 6-dihydro-pyridin-3-yl } -phenyl) -2H-isoquinolin-1-one and other molecules capable of inhibiting BTK activity, e.g., akineley et ah, journal of Hematology&BTK inhibitors of those disclosed in Oncology,2013,6:59, the entire contents of which are incorporated herein by reference.
Syk inhibitors include, but are not limited to, cerdulatinib (4- (cyclopropylamino) -2- ((4- (4- (ethylsulfonyl) piperazin-1-yl) phenyl) amino) pyrimidine-5-carboxamide), entospletinib (6- (1H-indazol-6-yl) -N- (4-morpholinophenyl) imidazo [1,2-a ] pyrazin-8-amine), fostaninib (fostaminib) ([ 6- ({ 5-fluoro-2- [ (3, 4, 5-trimethoxyphenyl) amino ] -4-pyrimidinyl } amino) -2, 2-dimethyl-3-oxo-2, 3-dihydro-4H-pyrido [3,2-b ] [1,4] oxazin-4-yl ] methyldihydro-phosphate), fostaninib disodium ((6- ((5-fluoro-2- ((3, 4, 5-trimethoxyphenyl) amino) pyrimidin-4-yl) amino) -2, 2-dimethyl-3-oxo-2H-pyrido [3, 2-dimethyl-3-oxo-2-pyrido [3, 4-yl ] pyrimidine-4-amino), sodium salt of fostaninib ((6- ((5-fluoro-2- ((3, 4, 5-trimethoxyphenyl) amino) pyrimidine-4-yl) amino), and sodium of (1, 4-yl) amino) -7-pyrido [3, 4-methyl ] amino-7-amino-7-yl-methyl-pyrimidine-carboxamide RO9021 (6- [ (1R, 2S) -2-amino-cyclohexylamino ] -4- (5, 6-dimethyl-pyridin-2-ylamino) -pyridazine-3-carboxylic acid amide), imatinib (Gleeva; 4- [ (4-methylpiperazin-1-yl) methyl ] -N- (4-methyl-3- { [4- (pyridin-3-yl) pyrimidin-2-yl ] amino } phenyl) benzamide), staurosporine, GSK143 (2- (((3R, 4R) -3-aminotetralin-2H-pyran-4-yl) amino) -4- (p-tolylamino) pyrimidine-5-carboxamide), PP2 (1- (tert-butyl) -3- (4-chlorophenyl) -1H-pyrazolo [3,4-d ] pyrimidine-4-amine), PRT-060318 (2- (((1R, 2S) -2-aminocyclohexyl) amino) -4- (m-tolylamino) pyrimidine-5-carboxamide), PRT-062607 (4- ((3- (2H-1, 2, 3-triazol-2-yl) phenyl) amino) -2- (((1R, 2S) -2-aminocyclohexyl) amino) pyrimidine-5-carboxamide hydrochloride), R112 (3, 3' - ((5-fluoropyrimidin-2, 4-diyl) bis (azanediyl)) diphenol), R348 (3-ethyl-4-methylpyridine), R406 (6- ((5-fluoro-2- ((3, 4, 5-trimethoxyphenyl) amino) pyrimidin-4-yl) amino) -2, 2-dimethyl-2H-pyrido [3,2-b ] [1,4] oxazin-3 (4H) -one), piceatannol (3-hydroxyresveratrol), YM193306 (see Singh et al Discovery and Development of Spleen Tyrosine Kinase (SYK) inhibit, jmed.chem.2012, 55, 3614-3643), 7-azaindole, piceatannol, ER-27319 (see Singh et al Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, j.med.chem.2012,55,3614-3643, the entire contents of which are incorporated herein), compound D (see Singh et al Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, j.med.chem.2012,55,3614-3643, the entire contents of which are incorporated herein), PRT060318 (see Singh et al Discovery and Development of Spleen Tyrosine Kinase (SYK) Inhibitors, j.med.chem.2012,55,3614-3643, which is incorporated herein in its entirety), luteolin (see Singh et al Discovery and Development of Spleen Tyrosine Kinase (SYK) inhibit, j.med.chem 2012,55,3614-3643, which is incorporated herein in its entirety), apigenin (see Singh et al Discovery and Development of Spleen Tyrosine Kinase (SYK) inhibit, j.med.chem 2012,55,3614-3643, which is incorporated herein in its entirety), quercetin (see Singh et al Discoveryand Development of Spleen Tyrosine Kinase (SYK) inhibit, j.med.chem 2012,55,3614-3643, which is incorporated herein in its entirety), fisetin (see Singh et al Discovery and Development of Spleen Tyrosine Kinase (SYK) inhibit, j.med.chem 2012,55,3614-3643, which is incorporated herein in its entirety), myricetin (see Singh et al Discovery and Development of Spleen Tyrosine Kinase (SYK) inhibit, j.2012, 3614-3643, which is incorporated herein in its entirety), and/or fisetin (see Singh et al) inhibit, j.2012, j.med.3614-3643, which is incorporated herein in its entirety), and (see Singh et al, j.3656, chem) inhibit, j.3643, which is incorporated herein in its entirety.
In certain embodiments, the bioactive agent is a MEK inhibitor. MEK inhibitors are well known and include, for example, trametetinib/GSKl 120212 (N- (3- { 3-cyclopropyl-5- [ (2-fluoro-4-iodophenyl) amino ] -6, 8-dimethyl-2, 4, 7-trioxo-3, 4,6, 7-tetrahydropyrido [4,3-d ] pyrimidin-l (2H-yl } phenyl) acetamide), semmetinib (selumetinib) (6- (4-bromo-2-chloroanilino) -7-fluoro-N- (2-hydroxyethoxy) -3-methylbenzimidazole-5-carboxamide), pimasertib/AS703026/MSC1935369 ((S) -N- (2, 3-dihydroxypropyl) -3- ((2-fluoro-4-iodophenyl) amino) isonicotinamide), XL-518/GDC-0973 (l- ({ 3, 4-difluoro-2- [ (2-fluoro-4-iodophenyl) amino ] phenyl } carbonyl) -3- [ (2S) -piperidin-2-yl ] azetidin-3-ol), rafacitinib (refametinib)/BAY 869766/RDEAl 19 (N- (3, 4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide), PD-0325901 (N- [ (2R) -2, 3-dihydroxypropoxy ] -3, 4-difluoro-2- [ (2-fluoro-4-iodophenyl) amino ] -benzamide), TAK733 ((R) -3- (2, 3-dihydroxypropyl) -6-fluoro-5- (2-fluoro-4-iodophenylamino) -8-methylpyrido [2,3-d ] pyrimidine-4, 7 (3H, 8H) -dione), MEK162/ARRY438162 (5- [ (4-bromo-2-fluorophenyl) amino ] -4-fluoro-N- (2-hydroxyethoxy) -1-methyl-1H-6-carboxamide), R05126766 (3-fluoro-2- (2-methylsulfamoyl) -amino ] -4-pyridone, W554-methyl-5-pyrido [2,3-d ] pyrimidine-4, 7 (3H, 8H) -dione), MEK162/ARRY438162 (5- [ (4-bromo-2-fluorophenyl) amino ] -4-fluoro-N- (2-hydroxyethoxy) -1-methyl-1H-6-carboxamide), R05126766 (3-fluoro-2- (2-fluoro-4-iodophenylamino) -6-methyl-pyridone, R-3-fluoro-5-fluoro-4-amino ] -pyrido-1-yl-1-yl-methyl-1-yl-1-e R04987655/CH 4987555 (3, 4-difluoro-2- ((2-fluoro-4-iodophenyl) amino) -N- (2-hydroxyethoxy) -5- ((3-oxo-l, 2-oxazinan-2-yl) methyl) benzamide) or AZD8330 (2- ((2-fluoro-4-iodophenyl) amino) -N- (2-hydroxyethoxy) -1, 5-dimethyl-6-oxo-l, 6-dihydropyridine-3-carboxamide), U0126-EtOH, PD184352 (CI-1040), GDC-0623, BI-847325, cobratinib, PD98059, BIX 02189, BIX 02188, bimetinib, SL-327, TAK-733, PD318088.
In certain embodiments, the bioactive agent is a Raf inhibitor. Raf inhibitors are known and include, for example, vemurafinib (N- [3- [ [5- (4-chlorophenyl) -1H-pyrrolo [2,3-b ] pyridin-3-yl ] carbonyl ] -2, 4-difluorophenyl ] -1-propanesulfonamide), sorafenib tosylate (4- [4- [ [ 4-chloro-3- (trifluoromethyl) phenyl ] carbamoylamino ] phenoxy ] -N-methylpyridin-2-carboxamide 4-methylbenzenesulfonate), AZ628 (3- (2-cyanopropan-2-yl) -N- (4-methyl-3- (3-methyl-4-oxo-3, 4-dihydro-quinazolin-6-ylamino) phenyl) benzamide), NVP-BHG712 (4-methyl-3- (1-methyl-6- (pyridin-3-yl) -1H-pyrazolo [3,4-d ] pyrimidin-4-ylamino) -N- (3- (trifluoromethyl) phenyl) benzamide), RAF-265 (1-methyl-5- [2- [5- (trifluoromethyl) -1H-imidazol-2-yl ] pyridin-4-yl ] oxy-N- [4- (trifluoromethyl) phenyl ] benzimidazol-2-amine), 2-Bromoaldisine (2-bromo-6, 7-dihydro-1H, 5H-pyrrolo [2,3-c ] aza-table-4, 8-dione), RAF kinase inhibitor IV (2-chloro-5- (2-phenyl-5- (pyridin-4-yl) -1H-imidazol-4-yl) phenol), sorafenib N-oxide (4- [4- [ [ [ 4-chloro-3 (trifluoromethyl) phenyl ] amino ] carbonyl ] amino ] phenoxy ] -N-methyl-2-pyridinecarboxamide 1-oxide), PLX-4720, darafinib (GSK 2118436), GDC-0879, RAF265, AZ628, SB590885, ZM336372, GW5074, TAK-818, TAK 35858 84 and gχ (gχ 35).
In certain embodiments, the bioactive agent is an AKT inhibitor, including but not limited to MK-2206, GSK690693, pirifaction, (KRX-0401), GDC-0068, troxiribine, AZD5363, and magnolol, PF-04691502, and miltefosine (an FLT-3 inhibitor), including but not limited to P406, duob Wei Tini, quinidine (AC 220), amuvatib (MP-470), tandutinib (MLN 518), ENMD-2076, and KW-2449, or combinations thereof.
In certain embodiments, the bioactive agent is an mTOR inhibitor. Examples of mTOR inhibitors include, but are not limited to, rapamycin and analogs thereof, everolimus (Afinitor), temsirolimus, li Dafu limus (ridaforolimus), sirolimus, and delforsolimus (deforolimus). Examples of MEK inhibitors include, but are not limited to, trametetinib/GSKl 120212 (N- (3- { 3-cyclopropyl-5- [ (2-fluoro-4-iodophenyl) amino ] -6, 8-dimethyl-2, 4, 7-trioxo-3, 4,6, 7-tetrahydropyrido [4,3-d ] pyrimidin-l (2H-yl } phenyl) acetamide), semmetinib (selumetidinob) (6- (4-bromo-2-chloroanilino) -7-fluoro-N- (2-hydroxyethoxy) -3-methylbenzimidazole-5-carboxamide), pimasertib/AS703026/MSC1935369 ((S) -N- (2, 3-dihydroxypropyl) -3- ((2-fluoro-4-iodophenyl) amino) isonicotinamide), XL-518/GDC-0973 (l- ({ 3, 4-difluoro-2- [ (2-fluoro-4-iodophenyl) amino ] phenyl } carbonyl) -3- [ (2S) -piperidin-2-yl ] azetidin-3-ol) (cobalamide), rafatinib (refametinib)/BAY 869766/RDEAl19 (N- (3, 4-difluoro-2- (2-fluoro-4-iodophenylamino) -6-methoxyphenyl) -1- (2, 3-dihydroxypropyl) cyclopropane-1-sulfonamide), PD-0325901 (N- [ (2R) -2, 3-dihydroxypropoxy ] -3, 4-difluoro-2- [ (2-fluoro-4-iodophenyl) amino ] -benzamide), TAK733 ((R) -3- (2, 3-dihydroxypropyl) -6-fluoro-5- (2-fluoro-4-iodophenylamino) -8-methylpyrido [2,3d ] pyrimidine-4, 7 (3H, 8H) -dione), MEK162/ARRY438162 (5- [ (4-bromo-2-fluorophenyl) amino ] -4-fluoro-N- (2-hydroxyethoxy) -1-methyl-1H-benzimidazole-6-carboxamide), R05126766 (3-fluoro-2- (2-methylsulfamoyl) -amino ] -4-pyrid-yl ] pyrimidine-4-8-methylpyrido [2,3d ] pyrimidine-4-dione, 7 (3H, 8H) -dione), MEK162/ARRY438162 (5- [ (4-bromo-2-fluorophenyl) amino ] -4-fluoro-N- (2-hydroxyethoxy) -1H-benzimidazole-6-carboxamide), R04987655/CH 4987555 (3, 4-difluoro-2- ((2-fluoro-4-iodophenyl) amino) -N- (2-hydroxyethoxy) -5- ((3-oxo-l, 2-oxazinan-2-yl) methyl) benzamide) or AZD8330 (2- ((2-fluoro-4-iodophenyl) amino) -N- (2-hydroxyethoxy) -1, 5-dimethyl-6-oxo-l, 6-dihydropyridine-3-carboxamide).
In certain embodiments, the bioactive agent is an RAS inhibitor. Examples of RAS inhibitors include, but are not limited to, reolysin and siG D LODER.
In certain embodiments, the bioactive agent is an HSP inhibitor. HSP inhibitors include, but are not limited to, geldanamycin or 17-N-allylamino-17-demethoxygeldanamycin (17 AAG) and Radicicol.
Additional bioactive compounds include, for example, everolimus, trabectedin, abaxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, FLT-3 inhibitor, VEGFR inhibitor, aurora kinase inhibitor, PIK-1 modulator HDAC inhibitors, c-MET inhibitors, PARP inhibitors, cdk inhibitors, IGFR-TK inhibitors, anti-HGF antibodies, focal adhesion kinase inhibitors, map kinase (mek) inhibitors, VEGF trap antibodies, pemetrexed, panitumumab, amrubicin, ogoropamab, lep-etu, nolatrexed, 622171, batabalin, atumumab, zanolimumab, edotecarin, tetrandrine; lubitecan (rubtecan), paltoli, olimmersen (obimersen), tiximab, ipilimab, gossypol, bio 111, 131-I-TM-601, ALT-110, BIO 140, CC 8490, cilengitide, ji Ma Tikang, IL13-PE38QQR 、INO 1001、IPdR 1 KRX-0402, thioxanthone (lucanthone), LY317615, neodi (Neuraadiab), viterspan (Viterspan), rta 744, sdx, talampanel, atrasentan (atabrentan), xr 311, romidepsin (romidepsin), ADS-100380, sunitinib, 5-fluorouracil, vorinostat (vorinostat), etoposide, gemcitabine, doxorubicin liposomes, 5' -deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, plug Li Xili; PD0325901, AZD-6244, capecitabine, L-glutamic acid, N- [4- [2- (2-amino-4, 7-dihydro-4-oxo-1H-pyrrolo [2,3-d ]]Pyrimidin-5-yl) ethyl]Benzoyl compounds]Disodium salt heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrozole, exemestane, letrozole, DES (diethylstilbestrol), estradiol, estrogen, conjugated estrogens, bevacizumab, IMC-1C11, CHIR-258); 3- [5- (methylsulfonylpiperidinylmethyl) -indolyl-quinolone, vartalanib, AG-0137636, AVE-0005, goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, medroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutamide, nilutamide (nilutamide), megestrol acetate, CP-724714; TAK-165, HKI-272, erlotinib, lapatinib, calitinib (canertinib), ABX-EGF antibody, erbitux (erbitux), EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib; amifostine (amifostine), NVP-LAQ824, suberoylanilide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, amsacrine, anagrelide, L-asparaginase, BCG, doxorubicin, bleomycin, buserelin, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clophosphonate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludroxin, flucycloxaprine, fluzamide, glibenc (gleevac), gemcitabine, hydroxymustard, idarubicin, ifosfamide, imatinib, promelin, levamisole, lomustine, nitrogen mustard, cyproterone, and the like Melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pennisetum, plicamycin, she Fenm sodium (porfimer), procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, retinoic acid, vindesine, 13-cis-retinoic acid, phenylalanine nitrogen mustard, uracil nitrogen mustard, estramustine, altretamine, fluorouridine, 5-deoxyuridine, cytosine arabinoside, 6-mercaptopurine, deoxymitomycin, calcitriol, pentarubicin, mithramycin, vinorelbine, topotecan, razoxin, martizoxin, COL-3, novalac, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxifene, spironolactone, finasteride, cimetidine, trastuzumab, interleukin fusion toxin (denileukin diftitox), gefitinib, bortezomib (bortezimia), paclitaxel without polyoxyethylated castor oil, docetaxel, epothilone B, BMS-247550, BMS-310705, SU6668, EMD 121974-hydroxy tamoxifen, pipaxifene (pipendoxicene), ERA-923, acixifene, fulvestrant, aclidinxifene, lasofoxifene, indoxifene (TSE-424), HMR-3339, ZK186619, topotecan PTK787/ZK 584, VX-222352, 1845, rapamycin 40-O- (2-hydroxyethyl) -rapamycin, temsirolimus (temsirolimus), AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779,450, PEG-feaglutin, dabepoetin, erythropoietin, granulocyte colony stimulating factor, zoledronic acid, prednisone, cetuximab, granulocyte macrophage colony stimulating factor, histidine, PEGylated interferon alpha-2 a, PEGylated interferon alpha-2 b, azacytidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexanabine, all-trans-retinoic acid, ketone, interleukin-2, megestrol, Immunoglobulin, nitrogen mustard, methylprednisolone, ibritumomab (ibritgumomab tiuxetan), androgens, decitabine, altretamine, valsalbutamol, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, daunorubicin liposome, edwin-asparaginase, strontium 89, casteptan, netupitant, NK-1 receptor antagonists, palonosetron, aprepitant, diphenhydramine, hydroxyzine, methochlorprom, lorazepam, alprazolam, haloperidol, dronabinol, dexamethasone, methylprednisolone, prochloraz, granisetron, ondansetron, dolasetron, tropisetron, PEG febanzetin, erythropoietin, epothilone, dapoxetine alpha, and mixtures thereof.
In certain embodiments, the compound is administered in combination with ifosfamide.
In certain embodiments, the bioactive agent is selected from, but not limited to, imatinib mesylateDasatinib->Nilotinib->Bosutinib>Trastuzumabtrastuzumab-DM 1, pertuzumab (PerjetaTM), lapatinib +.>Gefitinib>Erlotinib>Cetuximab->PanitumumabVandetanib- >Vitamin Mo Feini->VorinostatRomidepsin->Bexarotene->Alisretinic acidTretinoin->Carfilzomib (Kyproliis TM), pralatrexed +.>Bevacizumab->Abelmosipu->Sorafenib->SunitinibPazopanib->Regorafenib->And cabatinib (CometriqTM).
In certain aspects, the bioactive agent is an anti-inflammatory agent, a chemotherapeutic agent, a radiation therapeutic agent, an additional therapeutic agent, or an immunosuppressant.
Suitable chemotherapeutic bioactive agents include, but are not limited to, radioactive molecules, toxins (also known as cytotoxins or cytotoxic agents), including any agents that are detrimental to cell viability, as well as liposomes or other vesicles containing chemotherapeutic compounds. Typical anticancer drugs include: vincristineOr vincristine liposome->Daunorubicin (daunorubicin or +)>) Or doxorubicin->Cytarabine (cytosine arabinoside, ara-C or +.>) L-asparaginase->Or PEG-L-asparaginase (pernasase or +.>) Etoposide (VP-16), teniposide +.>6-mercaptopurine (6-MP or) Methotrexate, cyclophosphamide +.>Prednisone, dexamethasone (dexamethasone), imatinib +.>Dasatinib->Nilotinib->BosutinibAnd plaitinib (Iclusig) TM )。
Examples of additional suitable chemotherapeutic agents include, but are not limited to, 1-dehydrotestosterone, 5-fluorouracil dacarbazine, 6-mercaptopurine, 6-thioguanine, actinomycin D, doxorubicin, aclacin, alkylating agents, allopurinol sodium, altretamine, amifostine, anastrozole, amastatin (AMC)), antimitotics, cis-dichlorodiammine platinum (II) (DDP) cisplatin), diaminodichloroplatin, anthracyclines, antibiotics, antimetabolites, asparaginase, live BCG (intravesical), sodium betamethasone phosphate and betamethasone acetate, bicalutamide, bleomycin sulfate, busulfan, leucovorin calcium, calicheamicin, capecitabine, carboplatin, lomustine (CCNU), carmustine (BSNU), carmustine chlorambucil, cisplatin, cladribine, colchicine, conjugated estrogens, cyclophosphamide, cyotosphamide, cytarabine, cytochalasin B, cytoxan, dacarbazine, dactinomycin (formerly dactinomycin), daunorubicin hydrochloride, daunorubicin citrate (daunorucbicin citrate), diniinterleukin (denileukin diftitox), dexrazoxane, dibromomannitol, dihydroxyanthrax dione, docetaxel, dolasetron mesylate, doxorubicin hydrochloride, dronabinol, E.coli L-asparaginase, ipecac, epoetin-alpha, erwinia L-asparaginase, esterified estrogens, estradiol, sodium estramustine phosphate, ethidium bromide, ethinyl estradiol, etidronate, etoposide orange factor, etoposide, febuxostat, floxuridine, fluconazole, fludarabine phosphate, fluorouracil, flutamine, folinic acid, gemcitabine hydrochloride, glucocorticosteroid, goserelin acetate, gracilin D, granisetron hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, interferon alpha-2 b, irinotecan hydrochloride, letrozole, calcium leucovorin, leuprorelin acetate, levamisole hydrochloride, lidocaine, lomustine, maytansinoid, nitrogen mustard hydrochloride, medroxyprogesterone acetate, megestrol acetate, melphalan hydrochloride, mercaptopurine, mesna, methotrexate, methyltestosterone, mithramycin, mitomycin C, mitotane, mitoxantrone, nilutamide, octreotide acetate ondansetron hydrochloride, paclitaxel, disodium pamidronate, pennisetum hydrochloride, priomycin, polifeprosan with carmustine implant 20, porphin sodium, procaine, procarbazine hydrochloride, propranolol, rituximab, sand Mo Siting, streptozotocin, tamoxifen, paclitaxel, teniposide, testolactone, tetracaine, thiaepam chlorambucil, thioguanine, thiotepa, topotecan, toremifene, tretinoin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.
In some embodiments, the compounds of the invention are administered in combination with a chemotherapeutic agent (e.g., a cytotoxic agent or other chemical compound useful in treating cancer). Examples of chemotherapeutic agents include alkylating agents, antimetabolites, folic acid analogs, pyrimidine analogs, purine analogs and related inhibitors, vinca alkaloids, epipodophyllotoxins, antibiotics, L-asparaginase, topoisomerase inhibitors, interferons, platinum coordination complexes, anthracenedione substituted ureas, methylhydrazine derivatives, adrenocortical inhibitors, adrenocortical hormone, progesterone, estrogens, antiestrogens, androgens, antiandrogens and gonadotropin releasing hormone analogs. Also included are 5-fluorouracil (5-FU), calcium folinate (LV), irinotecan, oxaliplatin, capecitabine, paclitaxel and docetaxel. Non-limiting examples of chemotherapeutic agents include alkanesChemokines such as thiotepa and cyclophosphamide; alkyl sulfonates such as busulfan, imperoshu and piposulfan; chlorpropidines such as benzotepa, carboquinone, rituximab and uredept (uredopa); ethyleneimines and methylmelamines, including altretamine, tritamine, triethylenephosphoramide, triethylenethiophosphamide and trimethylol melamine; annonaceous acetogenins (especially bullatacin and bullatacin ketone); camptothecins (including the synthetic analog topotecan); bryostatin; calysistatin; CC-1065 (including adoxolone, calzelone and bizelone analogues thereof); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including synthetic analogs, KW-2189 and CB1-TM 1); elstuporin (eleutherobin); pancratistatin; glucurolactone (sarcodactylin); spongostatin (sponsin); nitrogen mustards such as chlorambucil, napthalene mustards, cholesteryl phosphoramide, estramustine, ifosfamide, mechlorethamine, oxaziridine hydrochloride, melphalan, mechlorethamine, melbinol, melphalan, triamcinolone acetonide, uracil mustards; nitroureas such as carmustine, chlorourectin, fotemustine, lomustine, nimustine and ranimustine (ranimustine); antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma ll and calicheamicin omega ll) (see, e.g., agnew, chem. Enti. Ed engl. 183-186 (1994)); anthracyclines (dynemicin), including dynemicin a; bisphosphonates, such as chlorophosphonate; epothilones; and new carcinostatin chromophores and related chromene diyne antibiotic chromophores), aclacinomycin, actinomycin, anthramycin (authamycin), azaserine, bleomycin, actinomycin C, carabicin, carminomycin, amphotericin, chromomycins, actinomycin D, daunorubicin, dithiin, 6-diazo-5-oxo-L-norleucine, (doxorubicin, including morpholino doxorubicin, cyanomorpholino doxorubicin, 2-pyrrolidodoxorubicin, and deoxydoxorubicin), epirubicin, eldrorubicin, idarubicin, doxycycline, mitomycin, e.g., silkSchizomycin C, norgamycin mycophenolic acid (nogalamycin), olivary mycin, pelomycin, potfiromycin, puromycin, three-iron doxorubicin, rodobicin, streptozotocin, tuberculin, ubenimex, clean statin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as dimethyl folic acid, methotrexate, pteroyltri-glutamic acid, trimethaumatic; purine analogs such as fludarabine, 6-mercaptopurine, thioadenine, thioguanine; pyrimidine analogs such as ambriseine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, fluorouridine; androgens such as carbosterone, hydroxymethylandrosterone propionate, epithiols, emandrane, and testosterone lactones; anti-adrenal properties such as aminoglutethimide, mantolbutamine, trilostane; folic acid supplements such as folinic acid; acetogenins; aldehyde phosphoramide glycosides; aminolevulinic acid; enuracil; amfenadine; bestabucil; a specific group; eda traxas; refofamine; dimecoxin; deaquinone; enonisole (elfomithin); hydroxy carbazole acetate; epothilone; eggshell robust; gallium nitrate; hydroxyurea; lentinan; lonidamine; maytansinoids such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mo Pai darol (mopidanmol); diamine nitroacridine; prastatin; nitrogen ammonia nitrogen mustard; pirarubicin; losoxantrone; podophylloic acid (podophyllinic acid); 2-ethyl hydrazide; procarbazine; / >Polysaccharide complex (JHS Natural Products, eugene, OR); carrying out a process of preparing the raw materials; rhizopus extract; cilaphland; germanium spiroamine; tenuazonic acid (tenuazonic acid); triiminoquinone; 2,2',2 "-trichlorotriethylamine; trichothecenes (especially T-2-mycin, veracurin a, cyclosporin a and serpentine; uratam; vindesine; dacarbazine; mannitol nitrogen mustard; dibromomannitol; dibromodulcitol; pipobromine; a gacytosine; cytarabine ("Ara-C"); cyclophosphamide; thiotepa; taxanes, e.g. jersey>(purple)Paclitaxel; bristol-Myers Squibb Oncology, prencton, N.J.), and->Albumin engineering nanoparticle formulations of paclitaxel without polyoxyethylated castor oil (American Pharmaceutical Partners, schaumberg, IL) and +.>Docetaxel (Rhone-Poulenc Rorer, antonny, france); chlorambucil; />Gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine;vinorelbine; no An Tuo; teniposide; eda traxas; daunorubicin; aminopterin; hilded; ibandronate; irinotecan (e.g., CPT-1 1); topoisomerase inhibitor RFS 2000; difluoromethyl ornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above. Two or more chemotherapeutic agents may be used in combination for administration in combination with the compounds of the present invention. Suitable dosing regimens for combination chemotherapy are known in the art. For example, combination dosing regimens are described in Saltz et al, proc.am.Soc.Clin.Oncol.18:233a (1999) and Douillard et al, lancet 355 (9209): 1041-1047 (2000).
Additional therapeutic agents that may be administered in combination with the compounds disclosed herein may include bevacizumab, sunitinib, sorafenib, 2-methoxyestradiol or 2ME2, finasteride, valproib, vandetanib, aflibercept, fu Luoxi mab, egrouitumumab (MEDI-522), cilengitide, erlotinib, cetuximab, panitumumab, gefitinib, trastuzumab, spinodal Wei Tini, phenytoin, atacicept, rituximab, alemtuzumab, aldesleukin, altlizumab, tolizumab, temsirolimus, everolimus, lu Kamu mab, daclizumab, HLL1, huN901-DM1, atimod, natalizumab, bortezomib, carzomib, ma Lizuo m, spiramycin saquinavir mesylate, ritonavir, nelfinavir mesylate, indinavir sulfate, belicastat, panobinostat, ma Pamu mab, lesimab, dulanamine, ABT-737, orlimarson, plitidepsin, talmapimod, P-00, enzastaurin, tipifarnib, pirifunew, imatinib, dasatinib, lenalidomide, thalidomide, simvastatin, celecoxib, bazedoxifene, AZD4547, rituximab, oxaliplatin (Eloxatin), PD0332991, rebaudimide (LEE 011), bomacenib (LY 2835219), HDM201, fulvestrant (Faslodex), exemestane (aromin), PIM, ruxotinib (INC 424), BGJ398, pexib, metrexed (almta), and ramucidant (IMC-1121B).
In certain embodiments, the additional treatment is a monoclonal antibody (MAb). Some mabs stimulate an immune response, thereby destroying cancer cells. Like antibodies naturally produced by B cells, these mabs may-coat the surface of cancer cells, thereby eliciting destruction of the immune system. For example, bevacizumab targets Vascular Endothelial Growth Factor (VEGF), a protein secreted by tumor cells and other cells in the tumor microenvironment that promotes the development of tumor blood vessels. When bound to bevacizumab, VEGF is unable to interact with its cellular receptor, thereby preventing signaling leading to the growth of new blood vessels. Similarly, cetuximab and panitumumab target the Epidermal Growth Factor Receptor (EGFR), while trastuzumab targets human epidermal growth factor receptor 2 (HER-2). MAbs that bind to cell surface growth factor receptors will prevent the targeting receptor from signaling its normal growth promotion. They may also trigger apoptosis and activate the immune system to destroy tumor cells.
In one aspect of the invention, the bioactive agent is an immunosuppressant. The immunosuppressant may be a calcineurin inhibitor, e.g. a cyclosporine or an ascomycin, e.g. cyclosporine a FK506 (tacrolimus), pimecrolimus, mTOR inhibitors, e.g. rapamycin or derivatives thereof, e.g. sirolimus +.>Everolimus->Tisirolimus, zotarolimus, grace-7, grace-9, rapamycin analogues, such as Li Dafu limus, azathioprine, campath 1H, S1P receptor modulators, such as fingolimod or analogues thereof, anti-IL-8 antibodies, mycophenolic acid or salts thereof, such as sodium salt, or prodrugs thereof, such as mycophenolate esters->OKT3(ORTHOCLONE/>) Prednisone, & gt>Sodium buconazole, OKT4, T10B9.A-3A, 33B3.1, 15-deoxyspergualin, trastumosi, leflunomide->CTLAI-Ig, anti-CD 25, anti-IL 2R, basiliximab +.>Dali bead mab->Mizoribine, methotrexate, dexamethasone, ISAtx-247, SDZ ASM 981 (pimecrolimus,/-A)>) CTLA4lg (abacet), bei Laxi pu, LFA3lg, etanercept (Immunex +.>Sold) adalimumabInfliximab->anti-LFA-1 antibodies, natalizumabEnmomab, golimumab, anti-thymic cell immunoglobulin, cetrimab, alfacalcidol, efalizumab, pride, mesalamine, aclidinium, codeine phosphate, pamphlet (benorilate), fenbufen, naproxen, diclofenac, etodolac, and indomethacin, aspirin, and ibuprofen.
In some embodiments, the bioactive agent is a therapeutic agent that is a biological agent such as a cytokine (e.g., an interferon or interleukin (e.g., IL-2)) for use in the treatment of cancer. In some embodiments, the biologic is an anti-angiogenic agent, such as an anti-VEGF agent, e.g., bevacizumabIn some embodiments, the biologic is an immunoglobulin-based biologic, e.g., a monoclonal antibody (e.g., a humanized antibody, a fully human antibody, an Fc fusion protein, or a functional fragment thereof) that agonizes a target to stimulate an anti-cancer response or antagonize an antigen important for cancer. Such agents include->(rituximab); />(dalizumab); />(basiliximab); />(palivizumab); />(infliximab);(trastuzumab); />(gemtuzumab ozagrel);(alemtuzumab); />(ibritumomab tikoxide); />(adalimumab); />(omalizumab); />(tositumomab-l-131); />(efalizumab); />(cetuximab); />(bevacizumab);(natalizumab); />(tobulab); />(panitumumab);(ranibizumab); />(ibuzumab); />(cetuximab);(golimumab); / >(kanamazumab); />(Wu Sinu mab);(ofatuzumab); />(Deshu mab); />(moviruximab);(Lei Xiku mab); />(belimumab); />(ipilimumab); />(bentuximab); />(pertuzumab); />(enmeltrastuzumab); and->(otophyllizumab). Antibody-drug conjugates are also included.
Combination therapies may include therapeutic agents that are non-drug therapies. For example, the compounds may be administered in addition to radiation therapy, cryotherapy, hyperthermia, and/or surgical excision of tumor tissue.
In certain embodiments, the first and second therapeutic agents are administered simultaneously or sequentially in either order. The first therapeutic agent may be administered immediately before or after the second therapeutic agent, at most 1 hour, at most 2 hours, at most 3 hours, at most 4 hours, at most 5 hours, at most 6 hours, at most 7 hours, at most 8 hours, at most 9 hours, at most 10 hours, at most 11 hours, at most 12 hours, at most 13 hours, at most 14 hours, at most 16 hours, at most 17 hours, at most 18 hours, at most 19 hours, at most 20 hours, at most 21 hours, at most 22 hours, at most 23 hours, at most 24 hours, or at most 1-7 days, 1-14 days, 1-21 days, or 1-30 days.
In certain embodiments, the second therapeutic agent is administered at a different dosage schedule than the compounds of the invention. For example, the second therapeutic agent may have a treatment holiday (treatment holiday) of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days per treatment cycle. In another embodiment, the first therapeutic agent has a treatment holiday. For example, the first therapeutic agent may have a treatment holiday of 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, or 14 days per treatment cycle. In certain embodiments, both the first and second therapeutic agents have a treatment holiday.
V. pharmaceutical composition
The compounds of formula I as described herein may be administered as pure chemicals, but more typically as pharmaceutical compositions, comprising an amount effective for a patient, typically a human, in need of such treatment to treat any of the disorders described herein. Accordingly, the present disclosure provides pharmaceutical compositions comprising an effective amount of a compound or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier for any of the uses described herein. The pharmaceutical composition may contain the compound or salt as the sole active agent, or in alternative embodiments, the compound and at least one additional active agent.
Generally, the compositions of the present disclosure will be administered in a therapeutically effective amount by any accepted mode of administration. The appropriate dosage range depends on numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication for which administration is aimed, and the preferences and experience of the relevant physician. One of ordinary skill in the art of treating such diseases will be able to determine a therapeutically effective amount of the presently disclosed compositions for a given disease without undue experimentation and relying on personal knowledge and the present disclosure.
In certain embodiments, the pharmaceutical composition is in a dosage form containing from about 0.005mg to about 2000mg, from about 1mg to about 1000mg, from about 10mg to about 800mg, or from about 20mg to about 600mg of the active compound and optionally from about 0.1mg to about 2000mg, from about 10mg to about 1000mg, from about 100mg to about 800mg, or from about 200mg to about 600mg of the additional active agent in a unit dosage form. Examples are dosage forms having at least about 0.005, 0.01, 0.025, 0.05, 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700 or 750mg of active compound or salt thereof and up to about 1 gram of active compound or salt thereof.
In certain embodiments, the pharmaceutical composition is in a dosage form containing from about 0.1mg to about 2000mg, from about 10mg to about 1000mg, from about 100mg to about 800mg, or from about 200mg to about 600mg of the active compound and optionally from about 0.1mg to about 2000mg, from about 10mg to about 1000mg, from about 100mg to about 800mg, or from about 200mg to about 600mg of the additional active agent in a unit dosage form. Examples are dosage forms having at least 0.1, 1, 5, 10, 25, 50, 100, 200, 250, 300, 400, 500, 600, 700 or 750mg of active compound or salt thereof.
In some embodiments, the compounds disclosed herein or used as described are administered once daily (QD), twice daily (BID), or three times daily (TID). In some embodiments, a compound disclosed herein or as used herein is administered at least once daily for at least 1 day, at least 2 days, at least 3 days, at least 4 days, at least 5 days, at least 6 days, at least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 15 days, at least 16 days, at least 17 days, at least 18 days, at least 19 days, at least 20 days, at least 21 days, at least 22 days, at least 23 days, at least 24 days, at least 25 days, at least 26 days, at least 27 days, at least 28 days, at least 29 days, at least 30 days, at least 31 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, or longer.
In certain embodiments, the compounds of the invention are administered once a day, twice a day, three times a day, or four times a day.
In certain embodiments, the compounds of the invention are administered orally once daily. In certain embodiments, the compounds of the invention are administered orally twice daily. In certain embodiments, the compounds of the invention are administered orally three times per day. In certain embodiments, the compounds of the invention are administered orally four times per day.
In certain embodiments, the compounds of the invention are administered intravenously once daily. In certain embodiments, the compounds of the invention are administered intravenously twice daily. In certain embodiments, the compounds of the invention are administered intravenously three times per day. In certain embodiments, the compounds of the invention are administered intravenously four times per day.
In some embodiments, administration of the compounds of the invention has a treatment holiday between treatment cycles. For example, a compound may have a treatment holiday of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days per treatment cycle.
In some embodiments, a loading dose is administered to begin treatment. For example, the compound may be administered at a dose at least about 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, 4.5x, 5x, 5.5x, 6x, 6.5x, 7x, 7.5x, 8x, 8.5x, 9x, 9.5x, or 10x higher than the maintenance dose treatment period to begin treatment. Additional exemplary loading doses include doses of at least about 1.5x, 2x, 2.5x, 3x, 3.5x, 4x, 4.5x, 5x, 5.5x, 6x, 6.5x, 7x, 7.5x, 8x, 8.5x, 9x, 9.5x, or 10x higher on the first 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days of treatment, followed by maintenance doses for the remaining days of treatment in the treatment cycle.
The pharmaceutical composition may also comprise a molar ratio of the active compound and the additional active agent. For example, the pharmaceutical composition may contain an anti-inflammatory agent or immunosuppressant in a molar ratio of about 0.5:1, about 1:1, about 2:1, about 3:1, or about 1.5:1 to about 4:1.
These compositions may contain any amount of active compound that achieves the desired result, for example, 0.1 to 99 weight percent (wt.%) compound, and typically at least about 5 wt.% compound. Some embodiments contain from about 25% to about 50% by weight or from about 5% to about 75% by weight of the compound.
A drug or therapeutically effective amount of the composition is delivered to a patient. The exact effective amount will vary from patient to patient and will depend on the species, age, size and health of the subject, the nature and extent of the patient being treated, the advice of the treating physician, and the therapeutic agent or combination of therapeutic agents selected for administration. The effective amount for a given situation can be determined by routine experimentation.
In certain embodiments, the therapeutic amount may be, for example, in the range of about 0.0001mg/kg to about 25mg/kg body weight. How many doses may be needed to administer to a subject to reduce and/or alleviate the sign, symptom, or etiology of the disorder under consideration, or to cause any other desired change in the biological system. When desired, formulations with enteric coatings suitable for sustained or controlled release administration of the active ingredient may be prepared.
In certain embodiments, the dosage is in the range of about 0.001-10mg/kg patient body weight, such as about 0.0001mg/kg, about 0.0005mg/kg, about 0.001mg/kg, about 0.005mg/kg, about 0.01mg/kg, about 0.05mg/kg, about 0.1mg/kg, about 0.15mg/kg, about 0.2mg/kg, about 0.25mg/kg, about 0.3mg/kg, about 0.35mg/kg, about 0.4mg/kg, about 0.45mg/kg, about 0.5mg/kg, about 1mg/kg, about 1.5mg/kg, about 2.0mg/kg, about 2.5mg/kg, about 3.0mg/kg, about 3.5mg/kg, about 4.0mg/kg, about 5.0mg/kg, about 5.5mg/kg, about 6.0mg/kg, about 6.45 mg/kg, about 0.5mg/kg, about 7.5mg/kg, about 9.9 mg/kg, about 0.5 mg/kg.
In certain embodiments, the therapeutic amount may be, for example, in the range of about 0.01mg/kg to about 250mg/kg body weight, more typically about 0.1mg/kg to about 10mg/kg. How many doses may be needed to administer to a subject to reduce and/or alleviate the sign, symptom, or etiology of the disorder under consideration, or to cause any other desired change in the biological system. When desired, formulations with enteric coatings suitable for sustained or controlled release administration of the active ingredient may be prepared.
In certain embodiments, the dose is in the range of about 0.01-100mg/kg patient body weight, such as about 0.01mg/kg, about 0.05mg/kg, about 0.1mg/kg, about 0.5mg/kg, about 1mg/kg, about 1.5mg/kg, about 2mg/kg, about 2.5mg/kg, about 3mg/kg, about 3.5mg/kg, about 4mg/kg, about 4.5mg/kg, about 5mg/kg, about 10mg/kg, about 15mg/kg, about 20mg/kg, about 25mg/kg, about 30mg/kg, about 35mg/kg, about 40mg/kg, about 45mg/kg, about 50mg/kg, about 55mg/kg, about 60mg/kg, about 65mg/kg, about 70mg/kg, about 75mg/kg, about 80mg/kg, about 85mg/kg, about 90mg/kg, about 95mg/kg, or about 100mg/kg.
The pharmaceutical formulation is preferably in unit dosage form. In such dosage forms, the formulation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged formulation containing discrete amounts of the formulation, such as tablets, capsules and powders packaged in vials or ampoules. In addition, the unit dosage form itself may be a capsule, tablet, cachet or lozenge, or it may be the packaging form of a suitable amount of any of these.
In certain embodiments, the compounds are administered as pharmaceutically acceptable salts. Non-limiting examples of pharmaceutically acceptable salts include: acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, and valerate. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium and magnesium and nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine and ethylamine.
Thus, the compositions of the present disclosure may be administered in pharmaceutical formulations, including pharmaceutical formulations suitable for oral (including buccal and sublingual), rectal, nasal, topical, transdermal, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous), injection, inhalation or spray, intra-aortic, intracranial, subdermal, intraperitoneal, subcutaneous or by other means of administration containing conventional pharmaceutically acceptable carriers. Typical modes of administration are oral, topical or intravenous, with convenient daily dosing regimens, which may be adjusted according to the degree of affliction.
Depending on the intended mode of administration, the pharmaceutical composition may be in the form of a solid, semi-solid or liquid dosage form, such as a tablet, suppository, pill, capsule, powder, liquid, syrup, suspension, cream, ointment, lotion, paste, gel, spray, aerosol, foam, or oil, injection or infusion solution, transdermal patch, subcutaneous patch, inhalation formulation, medical device, suppository, buccal or sublingual formulation, parenteral formulation or eye drops, or the like, preferably in unit dosage form suitable for single administration of precise dosages.
Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., effective amounts for the desired purpose. The composition will comprise an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier, and may additionally comprise other agents, adjuvants, diluents, buffers, and the like.
The carrier includes excipients and diluents, and must be of sufficiently high purity and sufficiently low toxicity so that it is suitable for administration to the patient being treated. The carrier may be inert or may have its own pharmaceutical benefits. The amount of carrier used in combination with the compound is sufficient to provide the actual amount of the application material per unit dose of the compound.
The class of carriers includes, but is not limited to, adjuvants, binders, buffers, colorants, diluents, disintegrants, excipients, emulsifiers, flavoring agents, gels, glidants, lubricants, preservatives, stabilizers, surfactants, solubilizing agents, tabletting agents, wetting agents, or solidifying materials.
Some carriers may be listed in more than one category, for example vegetable oils may be used as lubricants in some formulations and as diluents in other formulations.
Exemplary pharmaceutically acceptable carriers include sugar, starch, cellulose, powdered tragacanth, malt, gelatin; talc, petrolatum, lanolin, polyethylene glycols, alcohols, transdermal enhancers, and vegetable oils. The pharmaceutical compositions may contain an optional active agent that does not substantially interfere with the activity of the compounds of the present invention.
Some excipients include, but are not limited to, liquids such as water, saline, glycerol, polyethylene glycol, hyaluronic acid, ethanol, and the like. The compounds may be provided, for example, in the form of solids, liquids, spray-dried materials, microparticles, nanoparticles, controlled release systems, and the like, as desired for the therapeutic objectives. Excipients suitable for use in non-liquid formulations are also known to those skilled in the art. An exhaustive discussion of pharmaceutically acceptable excipients and salts is available in Remington's Pharmaceutical Sciences (18 th edition) (Easton, pennsylvania: mack Publishing Company, 1990).
In addition, auxiliary substances, such as wetting or emulsifying agents, biological buffer substances, surfactants, and the like, may be present in such vehicles. The biological buffer may be any solution that is pharmacologically acceptable and which provides the desired pH for the formulation, i.e., a pH in a physiologically acceptable range. Examples of buffer solutions include saline, phosphate buffered saline, tris buffered saline, hank's buffered saline, and the like.
For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. Compositions that can be administered as liquid medicaments can be prepared, for example, by dissolving, dispersing, etc. an active compound as described herein and optionally a pharmaceutical adjuvant in an excipient such as water, saline, aqueous dextrose, glycerol, ethanol, or the like, to form a solution or suspension. The pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, sodium triethanolamine acetate, triethanolamine oleate, and the like, if desired. Practical methods of preparing such dosage forms are known or will be apparent to those skilled in the art; see, for example, remington's Pharmaceutical Sciences, referenced above.
In yet another embodiment, there is provided the use of a permeation enhancer excipient comprising a polymer such as: polycations (chitosan and its quaternary derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, polyacrylic acid); and thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugates).
In certain embodiments, the excipient is selected from the group consisting of Butylated Hydroxytoluene (BHT), calcium carbonate, calcium hydrogen phosphate, calcium stearate, croscarmellose, crospovidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl parahydroxybenzoate, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propyl parahydroxybenzoate, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin a, vitamin E, vitamin C, and xylitol.
The pharmaceutical composition/combination may be formulated for oral administration. For oral administration, the compositions are typically in the form of tablets, capsules, soft gel capsules, or may be aqueous or non-aqueous solutions, suspensions or syrups. Tablets and capsules are typical oral administration forms. Tablets and capsules for oral use may contain one or more of the usual carriers such as lactose and corn starch. A lubricant, such as magnesium stearate, is also typically added. In general, the compositions of the present disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like. In addition, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture, as desired or necessary. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, xanthan gum, and the like.
When a liquid suspension is used, the active agent may be combined with any orally acceptable, non-toxic, pharmaceutically acceptable inert carrier, such as ethanol, glycerol, water, and the like, as well as with emulsifying and suspending agents. Flavoring, coloring and/or sweetening agents may also be added if desired. Other optional components incorporated into the oral formulations herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.
For ocular delivery, the compound may be administered as desired, for example, via intravitreal, intrastromal, intracameral, sub-fascial, subretinal, retrobulbar, peribulbar, suprachoroidal (supraorbital), conjunctival, subconjunctival, episcleral, periocular, transscleral, retrobulbar, posterior juxtascleral (posterior juxtascleral), pericorneal or lacrimal injection, or by mucus, mucin or mucosal barrier, either in immediate or controlled release fashion or via ocular devices.
Parenteral formulations may be prepared in conventional form, either as liquid solutions or suspensions, as solids suitable for dissolution or suspension in a liquid prior to injection, or as emulsions. Generally, sterile injectable suspensions are formulated according to the techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in an acceptable non-toxic parenterally-acceptable diluent or solvent. Acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile, non-volatile oils, fatty esters or polyols are conventionally employed as a solvent or suspending medium. In addition, parenteral administration may involve the use of slow-release or sustained-release systems to maintain a constant dosage level.
Parenteral administration includes intra-articular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and includes aqueous and nonaqueous isotonic sterile injection solutions that may contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, as well as aqueous and nonaqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Administration via some parenteral routes may involve introducing the formulations of the present disclosure into a patient's body through a needle or catheter that is pushed by a sterile syringe or some other mechanical device such as a continuous infusion system. The formulations provided by the present disclosure may be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.
Formulations for parenteral administration according to the present disclosure include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils (such as olive oil and corn oil), gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. They may be sterilized, for example, by filtration through a bacterial-retaining filter (bacteria retaining filter), by introducing a sterilizing agent into the composition, by irradiating the composition, or by heating the composition. They may also be manufactured using sterile water or some other sterile injectable medium immediately prior to use.
Sterile injectable solutions are prepared by incorporating the disclosed compound(s) in the required amount in the appropriate solvent with various other ingredients enumerated above, as required, followed by filtered sterilization. Typically, dispersions are prepared by introducing the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the typical methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof. Thus, for example, a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of the active ingredient in 10% by volume of propylene glycol and water. The solution was isotonic with sodium chloride and sterilized.
Alternatively, the pharmaceutical compositions of the present disclosure may be administered in the form of suppositories for rectal administration. Suppositories can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents.
Formulations for buccal administration include tablets, troches, gels, and the like. Alternatively, buccal administration may be accomplished using transmucosal delivery systems known to those skilled in the art. The compounds of the present disclosure may also be delivered through skin or mucosal tissue using conventional transdermal drug delivery systems, i.e., transdermal-patches, "wherein the agent is typically contained in a laminate structure for use as a drug delivery device to be affixed to a body surface. In such a configuration, the pharmaceutical composition is typically contained in a layer or reservoir "beneath the upper backing layer. The lamination device may contain a single reservoir, or it may contain multiple reservoirs. In certain embodiments, the reservoir comprises a pharmaceutically acceptable polymeric matrix of contact adhesive material for securing the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylene, polysiloxanes, polyisobutylene, polyacrylates, polyurethanes, and the like.
Alternatively, the drug-containing reservoir and the skin contact adhesive are present as separate and distinct layers, the adhesive underlying the reservoir may in this case be a polymer matrix as described above, or may be a liquid or gel reservoir, or may take other forms. The backing layer in these laminates, which acts as the upper surface of the device, acts as the primary structural element of the laminate structure and provides great flexibility to the device. The material selected for the backing layer should be substantially impermeable to the active agent and any other materials present.
The compositions of the present disclosure may be formulated for aerosol administration, particularly administration to the respiratory tract, including intranasal administration. The compound may, for example, typically have a small particle size, e.g., about 5 microns or less. Such particle sizes may be obtained by means known in the art, for example by micronization. The active ingredient is provided in a pressurized package with a suitable propellant such as a chlorofluorocarbon (CFC) such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. The dosage of the drug may be controlled by a metering valve.
Alternatively, the active ingredient may be provided in the form of a dry powder, for example a powder mixture of the compound in a suitable powder base such as lactose, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP). The powder carrier will form a gel in the nasal cavity. The powder composition may be present in unit dosage form, for example in a capsule or cartridge, for example a gelatin or blister pack, from which the powder may be administered by means of an inhaler.
Formulations suitable for rectal administration are generally presented as unit-dose suppositories. These suppositories may be prepared by mixing the active compound with one or more conventional solid carriers such as cocoa butter and then shaping the resulting mixture.
In certain embodiments, the pharmaceutical composition is suitable for topical application to the skin using the application modes defined above.
In certain embodiments, the pharmaceutical composition is suitable for transdermal administration and may be in a discrete patch adapted to remain in intimate contact with the epidermis of the recipient for an extended period of time. Formulations suitable for transdermal administration may also be delivered by iontophoresis (see, e.g., pharmaceutical Research (6): 318 (1986)) and are generally in the form of an optionally buffered aqueous solution of the active compound.
In certain embodiments, microneedle patches or devices are provided for delivering drugs through or into biological tissue, particularly skin. The microneedle patches or devices allow for the delivery of drugs at clinically relevant rates through or into the skin or other tissue barrier with minimal or no damage, pain, or irritation to the tissue.
Formulations suitable for administration to the lungs may be delivered by a wide range of passive breath-actuated and active power-actuated single/multi-dose Dry Powder Inhalers (DPIs). The devices most commonly used for respiratory delivery include nebulizers, metered dose inhalers, and dry powder inhalers. There are several types of atomizers available, including jet atomizers, ultrasonic atomizers, and vibrating screen atomizers. The choice of a suitable pulmonary delivery device depends on parameters such as the nature of the drug and its formulation, site of action and pathophysiology of the lung.
VI general Synthesis
The compounds described herein may be prepared by methods known to those skilled in the art. In one non-limiting example, the disclosed compounds can be prepared using the following scheme.
For convenience, compounds of the invention having stereocenters may be drawn without stereochemistry. Those skilled in the art will recognize that pure or enriched enantiomers and diastereomers may be prepared by methods known in the art. Examples of methods of obtaining optically active materials include at least the following:
i) Physical separation of crystals-a technique of manually separating macroscopic crystals of individual enantiomers. This technique can be used if crystals of individual enantiomers are present, i.e. the material is a agglomerate (agglomerate) and the crystals are visually distinct;
ii) simultaneous crystallization-a technique in which individual enantiomers are crystallized separately from a solution of racemates, only if the enantiomers are in the form of solid agglomerates;
iii) Enzymatic resolution-a technique of partially or completely separating racemates by the different reaction rates of enantiomers with enzymes;
iv) enzymatic asymmetric synthesis-a synthetic technique in which at least one step in the synthesis uses an enzymatic reaction to obtain a synthetic precursor of an enantiomerically pure or enriched desired enantiomer;
v) chemical asymmetric synthesis—a synthetic technique in which the desired enantiomer is synthesized from an achiral precursor under conditions that produce asymmetry (i.e., chirality) in the product, which can be achieved by chiral catalysts or chiral auxiliary;
vi) diastereoisomeric separation-a technique whereby a racemic compound is reacted with an enantiomerically pure reagent (chiral auxiliary) to convert the individual enantiomer into diastereoisomer. The diastereomers obtained are then separated by chromatography or crystallization by means of their now more pronounced structural differences, followed by removal of the chiral auxiliary to obtain the desired enantiomer;
vii) primary and secondary asymmetric transformations-diastereoisomers from racemates equilibrate rapidly to give quantitative advantages in solution of diastereoisomers from the desired enantiomer, wherein preferential crystallization of diastereoisomers from the desired enantiomer perturbs the equilibrium such that ultimately in principle all material is converted from the desired enantiomer to the crystalline diastereomer. The desired enantiomer is then released from the diastereomer;
viii) kinetic resolution-this technique refers to effecting partial or complete resolution of the racemate (or further resolution of the partially resolved compound) by means of different reaction rates of the enantiomer with chiral non-racemic reagents or catalysts under kinetic conditions;
ix) enantiospecific synthesis from a non-racemic precursor-synthesis techniques in which the desired enantiomer is obtained from a non-chiral starting material and in which the stereochemical integrity is not compromised or only minimally compromised during synthesis;
x) chiral liquid chromatography—a technique (including vial chiral HPLC) that separates enantiomers of racemates in a liquid mobile phase by means of their different interactions with a stationary phase. The stationary phase may be made of chiral material or the mobile phase may contain additional chiral material to excite different interactions;
xi) chiral gas chromatography-a technique whereby racemates are volatilized and enantiomers are separated by virtue of their different interactions in the gaseous mobile phase with a column containing a fixed non-racemic chiral adsorbent phase;
xii) extraction with chiral solvents-a technique for separating enantiomers by preferential dissolution of one enantiomer into a particular chiral solvent;
xiii) transport across chiral membranes-a technique to bring racemates into contact with a thin film barrier. The barrier typically separates two miscible fluids, one of which contains racemates, and a driving force such as concentration or pressure differential is such that transport across the membrane barrier is preferential. Separation occurs due to the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through;
xiv) in certain embodiments simulated moving bed chromatography is used. Commercially available chiral stationary phases are of a wide variety.
General synthesis scheme 1
In some aspects, compounds of formula I can be synthesized according to the schemes provided in general synthesis scheme 1. In step 1, intermediate 1 and 2 are reacted in the presence of a copper catalyst (e.g., copper (I) iodide, copper (I) chloride, or another copper catalyst suitable for Ullmann coupling conditions), a ligand (e.g., bipyridine, 1, 10-phenanthroline, dimethylethylenediamine, or another ligand suitable for Ullmann coupling conditions), and a base (e.g., cesium carbonate, potassium carbonate, tripotassium phosphate, or another base suitable for Ullmann coupling conditions) at elevated temperatures to give 3 in an organic solvent (e.g., dimethyl sulfoxide, acetonitrile, or dioxane). In step 2, 3 is reacted with triphosgene in methylene chloride in the presence of aluminum trichloride to give 4. In step 3, intermediate 4 is reacted with a base (e.g., sodium hydride) in an organic solvent (e.g., tetrahydrofuran or methylene chloride) and then 5 is added to give 6.
General synthesis scheme 2
In some aspects, compounds of formula I can be synthesized according to the schemes provided in general synthesis scheme 2. In step 1, a catalyst is used in the presence of palladium (e.g., palladium (II) acetate, pd at elevated temperature 2 (dba) 3 Or another palladium catalyst suitable for Buchwald-Hartwig coupling conditions), a phosphine ligand (e.g., BINAP, xantPhos or another phosphine ligand suitable for Buchwald-Hartwig coupling conditions) and a base (e.g., potassium tert-butoxide, cesium carbonate or another base suitable for Buchwald-Hartwig coupling conditions) in the presence of an organic solvent (e.g., toluene, THF, dioxane or DMF) to afford 3.
General synthesis scheme 3
In some aspects, compounds of formula I can be synthesized according to the schemes provided in general synthesis scheme 3. In step 1, a catalyst is used in the presence of a palladium catalyst (e.g. PdCl at elevated temperature 2 (dppf)、PdCl 2 (PPh 3 ) Or another palladium catalyst suitable for Miyaura coupling conditions), ligands (e.g. Xphos, PPh 3 Or another ligand suitable for Miyaura coupling conditions) and a base (e.g., potassium acetate, potassium ethoxide, potassium carbonate, or another base suitable for Miyaura coupling conditions) in the presence of an organic solvent (e.g., toluene, DMA, or dioxane) to afford 3. In step 2, intermediate 3 was reacted with EtOH at elevated temperature to give 4. In step 3, compound 4 is reacted with 5 in the presence of a copper catalyst (e.g., copper (II) bromide, copper (II) acetate, or another copper catalyst suitable for use in Chan-Lam coupling conditions) and a base (e.g., pyridine, 4-dimethylaminopyridine, potassium tert-butoxide, or another suitable base used in Chan-Lam coupling conditions) in ambient air to give 6 in an organic solvent (e.g., methanol, acetonitrile, or dichloromethane).
General synthesis scheme 4
In some aspects, the compounds of formula I can be synthesized according to the pathway provided in general synthetic scheme 4. In step 1, a catalyst (e.g., pd (OAc)) is reacted at elevated temperature over a palladium catalyst (e.g., pd (OAc) 2 、Pd(PPh 3 ) 4 Or another suitable palladium catalyst), ligands (e.g., P (P-MeOPh) 3 、PPh 3 、PCy 3 Or another suitable ligand), water and pivalic anhydride in the presence of water to react intermediates 1 and 2 in an organic solvent (e.g., dimethoxyethane, THF or toluene) to give 3.
General synthesis scheme 5
In some aspects, the compounds of formula I can be synthesized according to the pathway provided in general synthesis scheme 5. In step 1, intermediate 1 is reacted with a suitable carbonyl reducing agent (e.g., sodium borohydride) in an organic solvent (e.g., ethanol or methanol) to give 2.
General synthesis scheme 6
In some aspects, the compounds of formula I can be synthesized according to the pathway provided in general synthesis scheme 6. In step 1, intermediates 1 and 2 are combined in a suitable drying agent (e.g., molecular sieves or MgSO 4 ) In an organic solvent (e.g., methylene chloride or toluene) in the presence of a solvent to give 3. In step 2, the imine of 3 is reduced to an amino group with a suitable reducing agent.
General synthesis scheme 7
In some aspects, the compounds of formula I can be synthesized according to the pathway provided in general synthesis scheme 7. In step 1, a catalyst (e.g., pd (OAc)) is reacted at elevated temperature over a palladium catalyst (e.g., pd (OAc) 2 、Pd 2 dba 3 Or another palladium catalyst suitable for Suzuki coupling conditions), ligands (e.g. Xphos, PCy 3 Or another ligand suitable for use in Suzuki coupling conditions) and a base (e.g., sodium carbonate, tripotassium phosphate, potassium carbonate, or another base suitable for use in Suzuki coupling conditions) in an aqueous organic solvent (e.g., 10:1 toluene: water, 5:1 THF: water, or 1:1 ethanol: water) to afford 3.
General synthesis scheme 8
In some aspects, canThe compounds of formula 1 were synthesized according to the pathway provided in general synthesis scheme 8. In step 1, a catalyst (e.g., pd (OAc)) is pre-reacted with palladium at an elevated temperature 2 、Pd 2 dba 3 Or another palladium catalyst suitable for palladium-catalyzed carbonylation), a base (e.g., triethylamine, diisopropylethylamine, or another base suitable for palladium-catalyzed carbonylation), CO gas, and a ligand (e.g., xantphos, PCy) 3 Or another ligand suitable for palladium-catalyzed carbonylation) with intermediate 1 and intermediate 2 in an organic solvent (e.g., DMF) to give 3.
EXAMPLE 1 Compounds 1 and 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ cd ] indol-2 (1H) -one
Step 1 Synthesis of 2-chloro-1- (4, 8-dibromonaphthalen-1-yl) ethan-1-one A stirred solution of 1, 5-dibromonaphthalen (162 g,566.51 mmol) in DCE (2000 mL) was cooled to 0deg.C and 2-chloroacetyl chloride (83.18 g,736.46mmol,58.57 mL) was added dropwise. The resulting solution was stirred at 0deg.C for 15 min, followed by the addition of anhydrous aluminum chloride (98.20 g,736.46mmol,40.25 mL) in portions. The resulting reaction mixture was then slowly warmed to room temperature and stirred for 16 hours. After completion (monitored by TLC), the reaction mixture was poured into ice-cold water and extracted with DCM (twice). The combined organic extracts were further washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (100-200 silica; gradient: 0-5% EtOAc in hexane) afforded 2-chloro-1- (4, 8-dibromo-1-naphthyl) ketene as an off-white solid (150 g,390 mmol). Yield: 69%. 1 H NMR(d 6 -DMSO,400MHZ)δ8.36(dd,J＝8.48,0.72Hz,1H),8.11-8.07(m,2H),7.69(t,J＝8.04Hz,1H),7.59(d,J＝7.8Hz,1H),5.05(s,2H)；
Step 2, synthesizing 4, 8-dibromo-1-naphthoic acid, namely stirring at room temperature to 2To a solution of chloro-1- (4, 8-dibromo-1-naphthyl) ketene (151 g,416.62 mmol) in sulfuric acid (1.8L) was added sodium nitrite (30.27 g,438.75 mmol) and the resulting reaction mixture was stirred at 65℃for 45 minutes. After completion (monitored by TLC), the reaction mixture was poured into cold water (2 l) and the resulting solid was filtered off. The solid thus obtained was added to a 10% sodium carbonate solution (4 liters) and stirred at room temperature for 30 minutes. Filtering the mixture; the filtrate was carefully acidified with concentrated HCl with vigorous stirring and filtered again to remove insoluble impurities. The filtrate (aqueous) was then extracted with ethyl acetate (twice). The combined organic extracts were further washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 4, 8-dibromonaphthalene-1-carboxylic acid (110 g,299 mmol) as a light brown solid. Yield: 72%. 1 H NMR(d 6 -DMSO,400MHZ)δ13.48(br s,1H),8.33(d,J＝8.36Hz,1H),8.09(d,J＝7.4Hz,1H),8.01(d,J＝7.72Hz,1H),7.65(t,J＝8.0Hz,1H),7.59(d,J＝7.72Hz,1H)；LC MS[M-H] - 328.90.
Step 3 Synthesis of 5-bromobenzo [ cd ]]Indol-2 (1H) -one to a stirred suspension of 4, 8-dibromonaphthalene-1-carboxylic acid (65 g,196.99 mmol) in aqueous ammonia (700 mL) was added copper powder (3.25 g,51.22 mmol) and the resulting reaction mixture was stirred at 80℃for 2 hours. After completion (monitored by TLC), the reaction mixture was poured into ice-cooled water and slowly acidified with concentrated HCl (pH-2) with vigorous stirring. The resulting yellow precipitate was filtered off and further dried under reduced pressure to give 5-bromo-1H-benzo [ cd ] as a brown solid ]Indol-2-one (39 g,151.68 mmol). Yield: 77%. 1 H NMR(d 6 -DMSO,400MHZ)δ10.88(s,1H),8.05(d,J＝7.44Hz,1H),7.88(d,J＝7.4Hz,1H),7.61(t,J＝7.8Hz,1H),7.53(d,J＝8.56Hz,1H),7.04(d,J＝7.0Hz,1H)；LC MS[M+H] + 248.2,250.1.
Step 4 Synthesis of 3- (5-bromo-2-oxo-benzo [ cd ]]Indol-1 (2H) -yl) piperidine-2, 6-dione (Compound 1) is prepared by reacting 5-bromo-1H-benzo [ cd ]]A suspension of indol-2-one (25 g,100.78 mmol) in dry THF (250 mL) was added in portions sodium hydride (60% dispersion in mineral oil) (38.61 g,1.01 mol) while maintaining the temperature below 5 ℃. Once the addition was complete, the resulting mixture was slowly warmed to room temperature and stirred for 15 minutes. The reaction mixture was cooled again to3-bromopiperidine-2, 6-dione (96.75 g,503.88 mmol) was added in portions at 0deg.C. The resulting reaction mixture was heated at 70℃for 1 hour. After completion (monitored by TLC), the reaction mixture was slowly poured into crushed ice and extracted with ethyl acetate (×3). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was triturated with diethyl ether and pentane to give the desired compound 3- (5-bromo-2-oxo-benzo [ cd) as a pale yellow solid]Indol-1-yl) piperidine-2, 6-dione (16 g,34.27 mmol). Yield: 34%. 1 H NMR(d 6 -DMSO,400MHZ)δ11.14(s,1H),8.12(d,J＝7.48Hz,1H),7.99(d,J＝7.44Hz,1H),7.72-7.62(m,2H),7.26(d,J＝6.92Hz,1H),5.46(dd,J＝12.84,5.28Hz,1H),2.99-2.90(m,1H),2.81-2.63(m,2H),2.12-2.07(m,1H)；LC MS[M+H] + 359.07,361.02.
Step 5 Synthesis of 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ cd ]]Indol-2 (1H) -one to 5-bromo-1H-benzo [ cd ] with stirring ]To a solution of indol-2-one (200 mg, 806. Mu. Mol,1 eq) in 1,4 dioxane (10 mL) was added bis (pinacolato) diboron (307 mg,1.21mmol,1.5 eq) followed by the addition of fully dried potassium acetate (237 mg,2.42mmol,3 eq). The resulting reaction mixture was degassed thoroughly with argon for 15 minutes. Pd (dppf) Cl was then added 2 DCM (66 mg, 81. Mu. Mol,0.1 eq) and heating the reaction mixture at 100℃for 16 hours. After the reaction was complete (monitored by TLC), the reaction mixture was cooled to room temperature and filtered through a celite pad, washing with EtOAc. The combined filtrates were then washed with cold water, dried over sodium sulfate and concentrated under reduced pressure to give crude 5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-benzo [ cd ]]Indol-2-one (200 mg, 406. Mu. Mol,60% purity) is a crude brown gum which is used without further purification. The yield thereof was found to be 35%. LC MS [ M+H ]] + 296.2. Example 2.5-chloromethyl-1- (4-methoxy-benzyl) -1H-benzo [ cd ]]Indol-2-ones
Step 1 Synthesis of 5-bromo-1- (4-methoxy-benzyl) -1H-benzo [ cd ]]Indol-2-one 5-bromo-1H-benzo [ cd ] under stirring at 0deg.C]Indole compoundsTo a solution of 2-ketone (50.0 g, 201.284 mmol) in DMF (150 mL) was added sodium hydride (60% dispersion in mineral oil) (7.255 g, 302.294 mmol) and the reaction mixture was stirred at the same temperature for 30 min. 4-methoxybenzyl chloride (32.806 mL,241.8 mmol) was then added and the reaction mixture was slowly warmed to room temperature and stirred for an additional 30 minutes. After completion of the reaction (monitored by TLC), the reaction mass was quenched with crushed ice and extracted with EtOAc. The organic extract was further washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (100-200 silica; gradient: 0-1% EtOAc in DCM) afforded 5-bromo-1- (4-methoxy-benzyl) -1H-benzo [ cd ] as a yellow solid ]Indol-2-one (66 g,179.36 mmol). The yield was 89%. 1 H NMR(d 6 -DMSO,400MHZ)δ8.09(d,J＝7.44Hz,1H),7.98(d,J＝7.44Hz,1H),7.65-7.56(m,2H),7.32(d,J＝8.56Hz,2H),7.19(d,J＝6.96Hz,1H),6.87(d,J＝8.56Hz,2H),5.03(s,2H),3.69(s,3H)；LC MS[M+H] + 367.80,369.84.
Step 2 Synthesis of 1- (4-methoxy-benzyl) -5-vinyl-1H-benzo [ cd ]]Indol-2-one 5-bromo-1- (4-methoxy-benzyl) -1H-benzo [ cd ] with stirring]A solution of indol-2-one (66 g,179.348 mmol) in toluene (800 mL) was purged with argon for 20 minutes. Tributylvinyltin (55.037 mL,188.315 mmol), triphenylphosphine (2.352 g,8.967 mmol) and tetrakis (triphenylphosphine) palladium (10.363 g,8.967 mmol) were added and the reaction mixture was heated at 110℃for 16 h. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure and the crude product thus obtained was purified by column chromatography (100-200 silica; gradient: 0-20% EtOAc in hexane) to give 1- (4-methoxy-benzyl) -5-vinyl-1H-benzo [ cd) as a yellow solid]Indol-2-one (45 g,141.68 mmol). The yield was 79%. 1 H NMR(d 6 -DMSO,400MHZ)δ8.07-8.03(m,2H),7.85(d,J＝8.64Hz,1H),7.59-7.49(m,2H),7.31(d,J＝8.6Hz,2H),7.12(d,J＝7.12Hz,1H),6.87(d,J＝8.56Hz,2H),6.15(d,J＝17.44Hz,1H),5.66(d,J＝11.16Hz,1H),3.69(s,3H)；LC MS[M+H] + 316.02
Step 3 Synthesis of 1- (4-methoxy-benzyl) -2-oxo-1, 2-dihydro-benzo [ cd ]]Indole-5-carbaldehyde 1- (4-methoxy-benzyl) -5-vinyl-1H-benzo [ cd ] with stirring]Water of indol-2-one (45 g,112.5 mmol)To a solution of (100 mL) and THF (300 mL) was added 4% OsO 4 (572 mg, 507.35. Mu. Mol,14.3 mL) and the reaction mixture was stirred at room temperature for 20 minutes, then sodium periodate (60.157 g,281.25 mmol) was added. The resulting reaction mixture was then stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through celite bed and washed with THF and EtOAc. The collected filtrate was then dried over sodium sulfate and concentrated under reduced pressure to give 1- (4-methoxy-benzyl) -2-oxo-1, 2-dihydro-benzo [ cd ] as a brown solid ]Indole-5-carbaldehyde (28 g,87.75 mmol). Yield: 78%. 1 H NMR(d 6 -DMSO,400MHZ)δ10.48(s,1H),8.41(d,J＝7.12Hz,1H),8.37(d,J＝8.64Hz,1H),8.27(d,J＝7.08Hz,1H),7.65-7.61(m,1H),7.33(d,J＝8.6Hz,2H),7.18(d,J＝7.2Hz,1H),6.88(d,J＝8.6Hz,2H),5.03(s,2H),3.69(s,3H)；LC MS[M+H] + 317.98
Step 4 Synthesis of 5-hydroxymethyl-1- (4-methoxy-benzyl) -1H-benzo [ cd ]]Indol-2-one 1- (4-methoxy-benzyl) -2-oxo-1, 2-dihydro-benzo [ cd ] at 0deg.C]To a solution of indole-5-carbaldehyde (28 g,88.324 mmol) in methanol (250 mL) was slowly added sodium borohydride (10.024 g,264.984 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mass was concentrated under reduced pressure and slowly poured into crushed ice. The solid precipitate formed is filtered off and dried appropriately under reduced pressure. Purification by column chromatography (100-200 silica; gradient: 0-5% MeOH in DCM) gave 5-hydroxymethyl-1- (4-methoxy-benzyl) -1H-benzo [ cd ] as a yellow solid]Indol-2-one (22 g,68.89 mmol). The yield was 78%. 1 H NMR(d6-DMSO,400MHZ)δ8.05(d,J＝7.2Hz,1H),7.82(d,J＝7.12Hz,1H),7.70(d,J＝8.48Hz,1H),7.47(t,J＝7.84Hz,1H),7.30(d,J＝8.48Hz,2H),7.09(d,J＝7.12Hz,1H),6.87(d,J＝8.56Hz,2H),5.53(t,J＝5.52Hz,1H),5.05-5.02(m,4H),3.69(s,3H)；LC MS[M+H] + 319.8
Step 5 Synthesis of 5-chloromethyl-1- (4-methoxy-benzyl) -1H-benzo [ cd ]]Indol-2-one to 5-hydroxymethyl-1- (4-methoxy-benzyl) -1H-benzo [ cd ] under stirring at 0deg.C]To a suspension of indol-2-one (22 g,68.966 mmol) in DCM (350 mL) was added Et 3 N (28.837 mL,206.897 mmol) and methanesulfonylChlorine (206.897 mmol,16.015 mL) and the resulting reaction mixture was stirred at room temperature for 16 hours. After completion (monitored by TLC), the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated under reduced pressure to give 5-chloromethyl-1- (4-methoxy-benzyl) -1H-benzo [ cd ] as a yellow solid ]Indol-2-one (19 g,56.55 mmol). Yield: 82%. 1 H NMR(d 6 -DMSO,400MHZ)δ8.07(d,J＝7.12Hz,1H),7.90(d,J＝7.16Hz,1H),7.80(d,J＝8.6Hz,1H),7.55(t,J＝7.88Hz,1H),7.31(d,J＝8.6Hz,2H),7.13(d,J＝7.16Hz,1H),6.87(d,J＝8.6Hz,2H),5.30(s,2H),5.03(s,2H),3.69(s,3H)；
EXAMPLE 3 Synthesis of 3- (2-oxo-5-vinyl-benzo [ cd ] indol-1-yl) piperidine-2, 6-dione (Compound 2) 1- (2, 6-dioxo-3-piperidinyl) -2-oxo-benzo [ cd ] indole-5-carbaldehyde (Compound 3)
Step 1 Synthesis of 3- (2-oxo-5-vinyl-benzo [ cd ]]Indol-1-yl) piperidine-2, 6-dione (Compound 2) is prepared by stirring 3- (5-bromo-2-oxo-benzo [ cd)]Indol-1-yl) piperidine-2, 6-dione (20 g,55.68 mmol) in toluene (500 mL) was purged with argon for 20 min. Tributylvinyltin (22.95 g,72.39mmol,21.06 mL), triphenylphosphine (730.26 mg,2.78 mmol) and tetrakis (triphenylphosphine) palladium (3.22 g,2.78 mmol) were added and the reaction mixture was heated at 110℃for 16 h. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure and the crude product was purified by column chromatography (100-200 silica; gradient: 0-10% MeOH in DCM) to give 3- (2-oxo-5-vinyl-benzo [ cd) as a yellow solid]Indol-1-yl) piperidine-2, 6-dione (14.3 g,32.85 mmol). The yield was 59%. LC MS [ M+H ]] + 307.2
Step 2 Synthesis of 1- (2, 6-dioxo-3-piperidyl) -2-oxo-benzo [ cd ]]Indole-5-carbaldehyde to 3- (2-oxo-5-vinyl-benzo [ cd ] on stirring ]Indol-1-yl) piperidine-2, 6-dione (14 g,45.70 mmol) in water (12 mL) and THF (36 mL) was added 4% OsO 4 Aqueous solution (578mg, 507.35. Mu. Mol,2 mL) and the reaction mixture was stirred at room temperature for 20 minSodium periodate (24.44 g,114.26 mmol) was then added. The resulting reaction mixture was then stirred at room temperature for 4 hours. After the reaction was complete (monitored by TLC), the reaction mixture was filtered through celite bed, washing with 20% ipa in THF and DCM. The collected filtrate was then dried over sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography (100-200 silica; gradient: 0-5% MeOH in DCM) to give 1- (2, 6-dioxo-3-piperidinyl) -2-oxo-benzo [ cd) as a yellow solid]Indole-5-carbaldehyde (8 g,16.91 mmol). Yield: 37%. 1 HNMR(d6-DMSO,400MHZ)δ11.16(s,1H),10.52(s,1H),8.46-8.43(m,2H),8.31-8.30(m,1H),7.71-7.67(m,1H),7.27-7.25(m,1H),5.48(dd,J＝12.48,4.84Hz,1H),2.95-2.90(m,1H),2.79-2.74(m,1H),2.68-2.63(m,1H),2.13-2.08(m,1H)；LC MS[M+H] + 309.0.
Example 4.3- [5- (Benzylimino) -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 4), 3- (5-amino-2-oxo-benzo [ cd ] indol-1-yl) piperidine-2, 6-dione (Compound 4), and 3- (5-fluoro-2-oxo-benzo [ cd ] indol-1-yl) piperidine-2, 6-dione (Compound 5)
Step 1 Synthesis of 5- (benzhydryleneamino) -1H-benzo [ cd ]]Indol-2-one 5-bromo-1H-benzo [ cd ] with stirring]To a solution of indol-2-one (25 g,100.78 mmol) and benzophenone imine (36.53 g,201.55mmol,33.82 mL) in toluene (1500 mL) was added sodium tert-butoxide (29.05 g,302.33 mmol), and the resulting reaction mixture was degassed with argon for 10 minutes. (5-diphenylphosphino-9, 9-dimethyl-xanthen-4-yl) -diphenyl-phosphine (11.66 g,20.16 mmol) and (1E, 4E) -1, 5-diphenylpenta-1, 4-dien-3-one palladium (9.23 g,10.08 mmol) were then added and the reaction mixture was heated at 80℃for 16 hours. After completion of the reaction (monitored by TLC and LCMS), the reaction mixture was diluted with cold water and extracted with EtOAc (×2). The crude extract was then dried over sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography (100-200 silica; gradient: 0-20% EtOAc in hexane) to give 5- (benzhydryleneamino) -1 as a yellow solid H-benzo [ cd ]]Indol-2-one (20 g,41.31 mmol). Yield: 41%. LC MS [ M+H ]] + 349.40.
Step 2 Synthesis of 3- [5- (benzhydrylideneamino) -2-oxo-benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (Compound 4) to 5- (benzhydryleneamino) -1H-benzo [ cd ] under stirring at 0deg.C]To a suspension of indol-2-one (10 g,28.70 mmol) in THF (100 mL) was added sodium hydride (60% dispersion in mineral oil) (16.50 g,430.54 mmol) in portions. After the addition was complete, the reaction mixture was slowly warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled again to 0deg.C and 3-bromo-glutarimide (33.07 g,172.22 mmol) was added in portions. The reaction mixture was warmed again to room temperature and heated at 70 ℃ for 4 hours. After completion (monitored by TLC), the reaction mixture was slowly poured into crushed ice. The aqueous portion was extracted with ethyl acetate (×3) and the combined organic layers were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude product thus obtained was triturated with diethyl ether and pentane to give the desired compound 3- [5- (benzhydryleneamino) -2-oxo-benzo [ cd ] as a yellow solid]Indol-1-yl]Piperidine-2, 6-dione (10 g,21.81 mmol). Yield: 76%. LC MS [ M+H ]] + 460.0.
Step 3 Synthesis of 3- (5-amino-2-oxo-benzo [ cd ] ]Indol-1-yl) piperidine-2, 6-dione (Compound 4) is prepared by stirring 3- [5- (benzhydryleneamino) -2-oxo-benzo [ cd ]]Indol-1-yl]To a solution of piperidine-2, 6-dione (10 g,21.76 mmol) in THF (100 mL) was added 15mL of aqueous HCl (2N) and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion (monitored by TLC), the reaction mixture was concentrated to dryness and 20mL of HCl in 1, 4-dioxane (4N) was added and the reaction was stirred for 30 min. The reaction mixture was concentrated again to dryness and triturated with ether to remove impurities. The crude product was then basified with saturated sodium bicarbonate solution and washed with 30% etoac/hexanes. Insoluble material found at the junction of the aqueous and organic layers was filtered off and dried appropriately to give the desired compound 3- (5-amino-2-oxo-benzo [ cd) as a yellow solid]Indol-1-yl) piperidine-2, 6-dione (5.5 g,18.71 mmol). Yield: 86%. 1 H NMR(d 6 -DMSO,400MHZ)δ11.03(s,1H),7.78(d,J＝8.52Hz,1H),7.72(d,J＝7.88Hz,1H),7.29(t,J＝7.86Hz,1H),7.13(br s,2H),6.98(d,J＝7.2Hz,1H),6.73(d,J＝7.88Hz,1H),5.34(dd,J＝12.64,5.2Hz,1H),2.98-2.88(m,1H),2.76-2.69(m,1H),2.66-2.60(m,1H),2.03-1.98(m,1H)；LC MS[M+H] + 296.2.
Step 4 Synthesis of 3- (5-fluoro-2-oxo-benzo [ cd ]]Indol-1-yl) piperidine-2, 6-dione (Compound 5) is prepared by stirring 3- (5-amino-2-oxo-benzo [ cd ] at 0deg.C]An indole-1-yl) piperidine-2, 6-dione (4 g,13.55 mmol) in THF (8 mL) was added 48% trifluoroborane hydrofluoric acid salt (1.19 g,13.55mmol,40 mL) followed by a solution of sodium nitrite (2.80 g,40.64mmol,1.29 mL) in water (4 mL). After the addition was complete, the reaction mixture was stirred at this temperature for 1 hour, then sodium tetrafluoroborate (7.44 g,67.73mmol,3.01 mL) was added. The resulting reaction mixture was then warmed to room temperature and filtered off. The collected solid was further washed with diethyl ether and dried under high vacuum to give the corresponding diazonium salt as a brown solid. The resulting solid was then suspended in para-xylene (50 mL) and heated at 140 ℃ for 2 hours. After completion (monitored by TLC), the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography (100-200 silica; gradient: 0-15% EtOAc in hexane) to give 3- (5-fluoro-2-oxo-benzo [ cd) as a yellow solid ]Indol-1-yl) piperidine-2, 6-dione (2.2 g,7.18 mmol). Yield: 53%. 1 H NMR(d6-DMSO,400MHZ)δ11.14(s,1H),8.15-8.12(m,1H),7.71-7.69(m,1H),7.65-7.60(m,2H),7.26(d,J＝7.08Hz,1H),5.46(dd,J＝12.84,5.2Hz,1H),2.99-2.90(m,1H),2.80-2.73(m,1H),2.70-2.63(m,1H),2.13-2.12(m,1H)；LC MS[M+H] + 299.0
Example 5 general procedure for amine-containing tricycloglutarimide compounds:
3- (5-bromo-2-oxo-benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 1) is coupled to the appropriate amine. The isolation and purification steps provide amine-substituted compounds, such as compound 7-compound 16.
EXAMPLE 6 3- (2-oxo-5- (-2- (trifluoromethyl) pyrrolidin-1-yl) benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (Compound 6)
Step 1 Synthesis of 1- (2, 6-bis (benzyloxy) pyridin-3-yl) -5- (2- (trifluoromethyl) pyrrolidin-1-yl) benzo [ cd ]]Indol-2 (1H) -ones to 1- (2, 6-bis (benzyloxy) pyridin-3-yl) -5-bromobenzo [ cd ]]A stirred solution of indol-2 (1H) -one (200 mg, 372. Mu. Mol,1 eq) was added to the amine 2- (trifluoromethyl) pyrrolidine (51 mg, 372. Mu. Mol,1 eq), cs in THF/tBuOH (4 mL,1:1, 0.093M) 2 CO 3 (242mg,744μmol,2eq)、Pd 2 (dba) 3 (34 mg, 37. Mu. Mol,0.1 eq) and RuPhos (34 mg, 74. Mu. Mol,0.2 eq). The solution was then degassed with argon and the mixture was then heated to 90 ℃ for 16 hours. After completion of the reaction, the mixture was filtered through a frit and washed with EtOAc. The filtrate was then concentrated to a crude residue which was passed throughNormal phase column chromatography was purified with 0-100% etoac in hexanes to give 1- (2, 6-dibenzyloxy-3-pyridinyl) -5- [ (2S) -2- (trifluoromethyl) pyrrolidin-1-yl as a solid ]Benzo [ cd ]]Indol-2-ones (100 mg, 100. Mu. Mol). The yield was-27%. LC MS ES+ [ M+H ]] + 596.2.
Step 2 Synthesis of 3- (2-oxo-5- (2- (trifluoromethyl) pyrrolidin-1-yl) benzo [ cd)]Indole-1 (2H) -yl) piperidine-2, 6-dione (Compound 6) to a degassed stirred solid 1- (2, 6-dibenzyloxy-3-pyridinyl) -5- [ (2S) -2- (trifluoromethyl) pyrrolidin-1-yl]Benzo [ cd ]]To a solution of indol-2-one (100 mg, 100. Mu. Mol,1 eq) in EtOAc/EtOH (10 mL,1:1, 0.02M) was added Pd/C (178 mg,10% dry, 1mmol,10 eq) and then the hydrogen balloon was connected to the reaction vessel and the mixture stirred at room temperature for 16 hours. After completion of the reaction, the mixture was filtered through a pad of celite, and the filtrate was concentrated to a crude residue which was purified by RP-HPLC to give the product 3- (2-oxo-5- (2- (trifluoromethyl) pyrrolidin-1-yl) benzo [ cd)]Indol-1 (2H) -yl) piperidine-2, 6-dione (4 mg, 9.5. Mu. Mol). The yield was-6%. LC MS ES+ [ M+H ]] + 418.1.
Compound 8-compound 16 was prepared using the same procedure as described in example 6 for the preparation of 3- (2-oxo-5- (2- (trifluoromethyl) pyrrolidin-1-yl) benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 7) using the appropriate amine starting material from the table.
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EXAMPLE 7.3- (2-oxo-5- ((S) -2-phenylpyrrolidin-1-yl) benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (Compound 18)
To 3- (5-fluoro-2-oxo-benzo [ cd) under stirring]Indole-1 (2H) -yl) piperidine-2, 6-dione (compound 17) (50 mg, 167. Mu. Mol,1 eq) and (2S) -2-phenylpyrrolidine (25 mg, 167. Mu. Mol,1 eq) in DMSO (0.08M) was added potassium carbonate (46 mg, 335. Mu. Mol,2 eq), and the reaction mixture was degassed with argon and stirred at 90℃for 16 hours. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was filtered off and the filtrate was concentrated to a crude residue. The crude product thus obtained is passed throughPurification by normal phase column chromatography with 0-100% EtOAc in hexane afforded the product 3- (2-oxo-5- ((S) -2-phenylpyrrolidin-1-yl) benzo [ cd ] as a solid]Indol-1 (2H) -yl) piperidine-2, 6-dione (18 mg, 42. Mu. Mol). Yield: 43%. LC MS ES+ [ M+H ]] + 426.2.
Compound 19-compound 25 was prepared using the same procedure as described in example 7 for the preparation of 3- (2-oxo-5- ((S) -2-phenylpyrrolidin-1-yl) benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 18) using the appropriate amine starting material from the table.
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Example 8.3- (2-oxo-5- (2- (pyridin-3-yl) pyrrolidin-1-yl) benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (Compound 26)
Step 1 Synthesis of (S) -5- (2- (pyridin-3-yl) pyrrolidin-1-yl) benzo [ cd ] ]Indol-2 (1H) -ones to 5-bromobenzo [ cd ] with stirring]Indol-2 (1H) -one (200 mg, 806. Mu. Mol,1 eq) solution was added 3-pyrrolidin-2-ylpyridine (119 mg, 806. Mu. Mol,1 eq), cs in THF/tBuOH (4 mL,1:1, 0.093M) 2 CO 3 (525mg,1.61mmol,2eq)、Pd 2 (dba) 3 (74 mg, 81. Mu. Mol,0.1 eq) and RuPhos (75 mg, 161. Mu. Mol,0.2 eq). The solution was then degassed with argon and the mixture was then heated to 90 ℃ for 16 hours. After completion of the reaction, the mixture was filtered through a frit and washed with EtOAc. The filtrate was then concentrated to a crude residue which was passed throughPurification by normal phase column chromatography with 0-100% EtOAc in hexane afforded 5- [2- (3-pyridyl) pyrrolidin-1-yl as a solid]-1H-benzo [ cd ]]Indol-2-ones (90 mg, 241. Mu. Mol). Yield: 30%. LC MS ES+ [ M+H ]] + 316.1.
Step 2 Synthesis of 3- (2-oxo-5- (2- (pyridin-3-yl) pyrrolidin-1-yl) benzo [ cd ]]Indole-1 (2H) -yl) piperidine-2, 6-dione (Compound 26) to cooled 5- [2- (3-pyridinyl) pyrrolidin-1-yl]-1H-benzo [ cd ]]To a solution of indol-2-one (45 mg, 142. Mu. Mol,1 eq) in THF (10 mL, 0.01M) was added NaH (54 mg,1.43mmol,60% oil dispersion, 10 eq) in portions while maintaining the temperature below 5 ℃. After the addition was complete, the mixture was stirred at room temperature for another 15 minutes, then the mixture was cooled again to 0 ℃ and 3-bromo-piperidine-2, 6-dione (137 mg,713 μmol,5 eq) was added. The mixture was heated to 70 ℃ for 1 hour. After the reaction was completed, the mixture was cooled to 0 ℃ and quenched with ice water. The mixture was then extracted with EtOAc (3×). The combined organic layers were separated, dried over sodium sulfate and concentrated to give a crude residue which was purified by RP-HPLC to give 3- [ 2-oxo-5- [2- (3-pyridinyl) pyrrolidin-1-yl as a solid ]Benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (5.1 mg, 12. Mu. Mol). Yield: 8%. LC MS ES+ [ M+H ]] + 427.2.
Compound 27 was prepared using the same procedure as described in example 8 for the preparation of 3- (2-oxo-5- (2- (pyridin-3-yl) pyrrolidin-1-yl) benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 26) using the appropriate amine starting materials in the table.
Example 9.4- (1- (2, 6-Dioxopiperidin-3-yl) -2-oxo-1, 2-dihydrobenzo [ cd ] indol-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (Compound 28), 4- (1- (2, 6-dioxopiperidin-3-yl) -2-oxo-1, 2-dihydrobenzo [ cd ] indol-5-yl) piperidine-1-carboxylic acid tert-butyl ester (Compound 29) and 3- (2-oxo-5- (piperidin-4-yl) benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (Compound 30)
Step 1 Synthesis of 4- (1- (2, 6-dioxopiperidin-3-yl) -2-oxo-1, 2-dihydrobenzo [ cd ]]Indol-5-yl) -3, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester(Compound 28) 3- (5-bromo-2-oxo-benzo [ cd) at 25 ℃C]Indol-1-yl) piperidine-2, 6-dione (compound 1) (200 mg, 556.83. Mu. Mol) in DMF (3 mL) was added 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (206.61 mg, 668.20. Mu. Mol) and cesium fluoride (126.87 mg, 835.25. Mu. Mol, 30.79. Mu. L) and the reaction mixture was degassed with nitrogen for 5 min. Cyclopentyl (diphenyl) phosphane dichloromethane dichloropalladium iron (45.47 mg,55.68 μmol) was added and the reaction mixture was again degassed with nitrogen for 5 minutes. The reaction mixture was stirred at 80℃for 10 hours. The reaction was monitored by LCMS, after completion, the reaction mixture was cooled to room temperature, then poured onto water (10 mL), extracted with ethyl acetate (2 x 10 mL), washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The crude residue was purified by flash chromatography using 25g silica and 0-100% ethyl acetate in hexanes as eluent to give 4- [1- (2, 6-dioxo-3-piperidinyl) -2-oxo-benzo [ cd ] as a yellow solid ]Indol-5-yl]-3, 6-dihydro-2H-pyridine-1-carboxylic acid ester (compound 28) (105 mg, 179.46. Mu. Mol,32% yield). By passing through 1 HNMR and LCMS (m/z=462.0 [ m+h)]Purity 78%) confirmed the desired product.
Step 2 Synthesis of 4- [1- (2, 6-dioxo-3-piperidyl) -2-oxo-benzo [ cd ]]Indol-5-yl]Piperidine-1-carboxylic acid tert-butyl ester (Compound 29) was prepared at room temperature under nitrogen atmosphere to a solution containing 4- [1- (2, 6-dioxo-3-piperidyl) -2-oxo-benzo [ cd ] with stirring]Indol-5-yl]A25 mL single neck round bottom flask of a suspension of tert-butyl 3, 6-dihydro-2H-pyridine-1-carboxylate (compound 28) (170 mg, 368.36. Mu. Mol) in 1, 4-dioxane (10 mL) was charged with palladium hydroxide on charcoal, 20wt.%50% water (103.46 mg, 736.74. Mu. Mol). The resulting suspension was stirred at ambient temperature under a hydrogen atmosphere (balloon) for 16 hours. After complete consumption of starting material by TLC, the reaction mixture was filtered through a celite pad and the celite bed was washed with 1, 4-dioxane (10 mL) and 1:1etoac/DCM (20 mL). The combined filtrates were concentrated under reduced pressure to give a crude residue, which was taken up with Et 2 O (2X 15 mL) was triturated to give 4- [1- (2, 6-dioxo-3-piperidyl) -2-oxo-benzo [ cd ] as a yellow solid]Indol-5-yl]Piperidine-1-carboxylic acid ester (Compound 29) (155 mg, 238.56. Mu. Mol, 64) % yield). LCMS (ESI) m/z 408.3[ M+H ] t Bu] + .
Step 3 Synthesis of 3- [ 2-oxo-5- (4-piperidinyl) benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 30) to a stirred solution of 4- [1- (2, 6-dioxo-3-piperidinyl) -2-oxo-benzo [ cd ] indol-5-yl ] piperidine-1-carboxylic acid tert-butyl ester (Compound 29) (0.140 g, 302.03. Mu. Mol, 000) in DCM (3 mL) at 0deg.C was added TFA (413.27 mg,3.62mmol, 279.23. Mu.L). The reaction mixture was stirred at 25 ℃ for 2 hours. The progress of the reaction was monitored by LCMS/TLC. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The crude product was triturated with diethyl ether (20 mL) to give 3- [ 2-oxo-5- (4-piperidinyl) benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (compound 30) as a pale yellow solid (0.1 g, 244.90. Mu. Mol,81% yield). The product formed was confirmed by LCMS.
EXAMPLE 10 3- [5- (1-benzyl-4-piperidinyl) -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (compound 32):
to stirring 3- [ 2-oxo-5- (4-piperidinyl) benzo [ cd ]]Indol-1-yl]To a solution of piperidine-2, 6-dione (compound 31) (0.060 g, 150.05. Mu. Mol) in THF (2 mL) was added benzaldehyde (15.92 mg, 150.05. Mu. Mol) and then stirred for 10 minutes. Thereafter, triethylamine (30.37 mg, 300.10. Mu. Mol, 41.83. Mu.L) was added and the reaction mixture was stirred at room temperature for 30 minutes. Next, sodium cyanoborohydride (23.57 mg, 375.12. Mu. Mol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC, and after completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Eluting with 1-5% MeOH/DCM, and purifying the crude compound by column chromatography followed by preparative HPLC to give 3- [5- (1-benzyl-4-piperidinyl) -2-oxo-benzo [ cd ] as a yellow solid ]Indol-1-yl]Piperidine-2, 6-dione (compound 32) (8 mg, 16.75. Mu. Mol,11% yield). 1 HNMR(400MHz,DMSO-d6):δ11.11(s,1H),8.04-8.02(d,J＝8Hz,1H),7.84-7.82(d,J＝8Hz,1H),7.74-7.72(d,J＝8Hz,1H),7.55-7.51(m,1H),7.35-7.25(m,5H),7.15-7.13(s,J＝8Hz,1H),5.44-5.42(m 1H),3.56(s,2H),3.32-3.30(m,1H),3.02-2.97(m,3H),2.76-2.73(m,1H),2.66-2.63(m,1H),2.24-2.21(m,1H),2.07(m,1H),1.89-1.86(m,5H).LC-MS:(ES+)＝454.2[M+H]+
EXAMPLE 11.3- [5- [1- [ (2-methoxypyrimidin-5-yl) methyl ] -4-piperidinyl ] -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 33)
To stirring 3- [ 2-oxo-5- (4-piperidinyl) benzo [ cd ]]Indol-1-yl]A solution of piperidine-2, 6-dione (Compound 31) (0.060 g, 150.05. Mu. Mol) in THF (2 mL) was added triethylamine (30.37 mg, 300.10. Mu. Mol, 41.83. Mu. L) followed by 2-methoxypyrimidine-5-carbaldehyde (20.73 mg, 150.05. Mu. Mol). The solution was stirred for 30 minutes. Sodium cyanoborohydride (23.57 mg, 375.12. Mu. Mol) was added and the reaction was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC, and after the reaction was completed, the reaction mixture was diluted with ethyl acetate and washed with brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 1-5% MeOH/DCM to give 3- [5- [1- [ (2-methoxypyrimidin-5-yl) methyl ] as an off-white solid]-4-piperidinyl]-2-oxo-benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (compound 33) (10 mg, 20.25. Mu. Mol,13% yield). 1 HNMR(400MHz,DMSO-d6):δ11.11(s,1H),8.56(S,2H),8.04-8.02(d,J＝8Hz,1H),7.85-7.82(d,J＝12Hz,1H),7.73-7.71(d,J＝8Hz,1H),7.55-7.51(m,1H),7.15-7.13(d,J＝8Hz,1H),5.44-5.42(m,1H),3.91(s,3H),3.55-3.41(m,4H),2.98-2.96(m,3H),2.76-2.74(m,1H),2.66-2.62(m,1H),2.32-2.25(m,2H),2.09-2.08(m,1H),1.96-1.93(m,3H).LC-MS:(ES+)＝486.2[M+H]+
EXAMPLE 12 3- [5- [1- [ (3-morpholinosulfonylphenyl) methyl ] -4-piperidinyl ] -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (compound 34)
To stirring 3- [ 2-oxo-5- (4-piperidinyl) benzo [ cd ]]Indol-1-yl]A solution of piperidine-2, 6-dione (compound 31) (0.075 g, 187.56. Mu. Mol) in THF (5 mL) was added triethylamine (37.96 mg, 375.12. Mu. Mol, 52. Mu.L), followed by 3-morpholinosulfonylbenzaldehyde (47.88 mg, 187.56. Mu. Mol) and the reaction was stirred at room temperature for 30 minutes. Sodium cyanoborohydride (29.47 mg, 468.90. Mu. Mol) was added and stirring was continued for an additional 16 hours. The progress of the reaction was monitored by TLC, and after the reaction was completed, the mixture was dissolved in ethyl acetate. The solution was washed with sodium bicarbonate and then brine. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC chromatography to afford 3- [5- [1- [ (3-morpholinosulfonylphenyl) methyl ] as a yellow solid]-4-piperidinyl]-2-oxo-benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (compound 34) (32 mg, 52.70. Mu. Mol,28% yield). 1 HNMR(400MHz,DMSO-d6):δ11.10(s,1H),8.05-8.03(d,J＝8Hz,1H),7.85-7.82(d,J＝12Hz,1H),7.76-7.74(m,3H),7.55-7.51(m,2H),7.15-7.13(d,J＝8Hz,1H),5.45-5.41(m,1H),3.70(m,2H),3.62(m,4H),3.44(m,1H),2.99-2.97(m,3H),2.91-2.87(m,4H),2.77-2.76(m,1H),2.66-2.63(m,2H),2.32(m,2H),2.09-2.06(m,1H),1.88(m,4H).
LC-MS:(ES+)＝603.2[M+H]+
EXAMPLE 13.3- [5- [1- [ (3-fluoro-4-methyl-phenyl) methyl ] -4-piperidinyl ] -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (compound 35)
To stirring 3- [ 2-oxo-5- (4-piperidinyl) benzo [ cd ]]Indol-1-yl]To a solution of piperidine-2, 6-dione (compound 31) (75 mg, 187.56. Mu. Mol) in THF (2 mL) was added 3-fluoro-4-methyl-benzaldehyde (25.91 mg, 187.56. Mu. Mol, 22.93. Mu.L), followed by triethylamine (37.96 mg, 375.12. Mu. Mol, 52. Mu.L). The reaction mixture was then stirred at room temperature for 30 minutes, then sodium cyanoborohydride (29.47 mg, 468.90. Mu. Mol) was added, and the reaction mixture was stirred at room temperature for an additional 16 hours. The progress of the reaction was monitored by TLC, and after completion of the reaction, the mixture was dissolved Washed with sodium bicarbonate and brine in ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to provide the crude compound, which was purified by column chromatography (1-5% methanol/DCM) followed by preparative HPLC to give 3- [5- [1- [ (3-fluoro-4-methyl-phenyl) methyl ] as an off-white solid]-4-piperidinyl]-2-oxo-benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (compound 35) (6 mg, 11.74. Mu. Mol,6% yield). 1 HNMR(400MHz,DMSO-d6):δ11.12(s,1H),8.04-8.03(d,J＝4Hz,1H),7.84-7.82(d,J＝8Hz,1H),7.75-7.73(d,J＝8Hz,1H),7.53(m,1H),7.26-7.22(m,1H),7.15-7.07(m,3H),3.54(s,2H),3.39-3.30(m,2H),2.98-2.95(m,3H),2.76-2.73(m,1H),2.66-2.62(m,1H),2.21(m,4H),2.07(m,1H),1.85(m,4H)1.73(m,1H).LC-MS:(ES+)＝486.3[M+H]+
EXAMPLE 14.3- [5- [1- [ (2-morpholinopyrimidin-5-yl) methyl ] -4-piperidinyl ] -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 36)
To stirring 3- [ 2-oxo-5- (4-piperidinyl) benzo [ cd ]]Indol-1-yl]To a solution of piperidine-2, 6-dione (compound 31) (0.075 g, 187.56. Mu. Mol) in THF (5 mL) was added 2-morpholinopyrimidine-5-carbaldehyde (36.24 mg, 187.56. Mu. Mol) followed by triethylamine (37.96 mg, 375.12. Mu. Mol, 52.28. Mu.L). The reaction mixture was stirred at room temperature for 30 minutes, then sodium cyanoborohydride (29.47 mg, 468.90. Mu. Mol) was added. The reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC, and after the reaction was completed, the reaction mixture was dissolved in ethyl acetate, followed by washing with sodium bicarbonate and brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound obtained was purified by preparative HPLC to give 3- [5- [1- [ (2-morpholinopyrimidin-5-yl) methyl ] as a pale yellow solid ]-4-piperidinyl]-2-oxo-benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (compound 36) (25 mg, 45.48. Mu. Mol,24% yield). 1 HNMR(400MHz,DMSO-d6):δ11.08(s,1H),8.34(s,2H),8.04-8.02(d,J＝8Hz,1H),7.84-7.82(d,J＝8Hz,1H),7.72-7.70(d,J＝8Hz,1H),7.54-7.50(m,1H),7.15-7.13(d,J＝8Hz,1H),3.67-3.66(m,6H),3.34(s,2H),2.98-2.91(m,2H),2.79-2.73(m,1H),2.66(m,1H),2.62-2.59(m,1H),2.37-2.32(m,1H),2.22-2.20(m,2H),2.09(m,1H),1.98(m,1H),1.85-1.75(m,6H).LC-MS:(ES+)＝541.3[M+H]+
EXAMPLE 15.3- [5- [1- (1H-indazol-5-ylmethyl) -4-piperidinyl ] -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 37)
To stirring 3- [ 2-oxo-5- (4-piperidinyl) benzo [ cd ]]Indol-1-yl]To a solution of piperidine-2, 6-dione (compound 31) (0.075 g, 187.56. Mu. Mol) in THF (5 mL) was added triethylamine (37.96 mg, 375.12. Mu. Mol, 52.28. Mu.L). The reaction mixture was stirred at room temperature for 30 minutes, then sodium cyanoborohydride (29.47 mg, 468.90. Mu. Mol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC, and after the reaction was completed, the mixture was dissolved in ethyl acetate, washed with sodium bicarbonate and brine. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography (0-5% methanol/DCM) followed by preparative HPLC to give 3- [5- [1- (1H-indazol-5-ylmethyl) -4-piperidinyl as a pale yellow solid]-2-oxo-benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (compound 37) (30 mg, 58.49. Mu. Mol,31% yield, 96%). 1 HNMR(400MHz,DMSO-d6):δ13.01(s,1H),11.10(s,1H),8.04-8.03(m,2H),7.84-7.82(m,1H),7.73-7.71(m,2H),7.55-7.51(m,2H),7.39-7.37(m,1H),7.15-7.13(d,J＝8Hz,1H),5.45-5.41(m,1H),3.70(s,2H),3.44(m,1H),3.05(m,2H),2.97-2.91(m,1H),2.79-2.73(m,1H),2.66-2.62(m,2H),2.32(m,2H),2.09-2.07(m,1H),1.88(m,3H).
LC-MS:(ES+)＝494.2[M+H]+
EXAMPLE 16.3- [5- [1- (1H-indol-2-ylmethyl) -4-piperidinyl ] -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 38)
To stirring 3- [ 2-oxo-5- (4-piperidinyl) benzo [ cd ]]Indol-1-yl]A solution of piperidine-2, 6-dione (compound 31) (0.090 g, 225.07. Mu. Mol) in THF (5 mL) was added triethylamine (45.55 mg, 450.15. Mu. Mol, 62.74. Mu. L) followed by 1H-indole-2-carbaldehyde (39.21 mg, 270.09. Mu. Mol), phenylsilane (121.78 mg,1.13 mmol) and dibutyltin dichloride (341.94 mg,1.13 mmol). The reaction was stirred at 60℃for 16 hours. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was dissolved in ethyl acetate, and then washed with sodium bicarbonate, followed by brine. The organic layer was separated and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by preparative HPLC to give 3- [5- [1- (1H-indol-2-ylmethyl) -4-piperidinyl ] as a yellow solid]-2-oxo-benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (compound 38) (24 mg, 46.90. Mu. Mol,20% yield). 1 HNMR(400MHz,DMSO-d6):δ11.10(brs,1H),11.01(s,1H),8.05-8.03(d,J＝8Hz,1H),7.85-7.82(d,J＝12Hz,1H),7.72-7.70(d,J＝8Hz,1H),7.54-7.50(m,1H),7.46-7.44(d,J＝6Hz,1H),7.34-7.32(d,J＝8Hz,1H),7.15-7.13(d,J＝8Hz,1H),7.04-7.00(m,1H),6.96-6.92(m,1H),6.30(s,1H),5.45-5.41(m,1H),3.71(s,2H),3.42-3.40(m,2H),3.06-3.03(m,2H),2.98-2.97(m,1H),2.91-2.90(m,1H),2.69-2.60(m,1H),2.31-2.27(m,1H),2.09-2.06(m,1H),1.90-1.88(m,4H).LC-MS:(ES+)＝493.2[M+H]+
EXAMPLE 17.3- [5- [1- (1H-indazol-4-ylmethyl) -4-piperidinyl ] -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 39)
To stirring 3- [ 2-oxo-5- (4-piperidinyl) benzo [ cd ]]Indol-1-yl]A solution of piperidine-2, 6-dione (Compound 39) (0.075 g, 187.56. Mu. Mol) in THF (5 mL) was added triethylamine (37.96 mg, 375.12. Mu. Mol, 52.28. Mu.L) and the reaction stirred for 30 min. After that, sodium cyanoborohydride (29.47 mg, 468.90. Mu. Mol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC, after completion of the reaction, the reaction mixture was dissolved in ethyl acetate, washed with sodium bicarbonate and brine. The organic matter is separated from the organic matter, Dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound. The crude material was purified by silica gel column chromatography (0-5% methanol/DCM) followed by preparative HPLC to give 3- [5- [1- (1H-indazol-4-ylmethyl) -4-piperidinyl as a pale yellow solid]-2-oxo-benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (Compound 39) (11 mg, 22.07. Mu. Mol,11% yield). 1 HNMR(400MHz,DMSO-d6):δ13.04(s,1H),11.12(s,1H),8.30(s,1H),8.04-8.03(d,J＝4Hz,1H),7.84-7.82(d,J＝8Hz,1H),7.75-7.74(d,J＝4Hz,1H),7.55-7.51(m,1H),7.44-7.42(m,1H),7.31-7.29(m,1H),7.15-7.13(m,1H),7.08(m,1H),5.44-5.43(m,1H),3.88(s,2H),3.42(m,1H),3.03(m,2H),2.94-2.91(m,1H),2.86-2.80(m,1H),2.76-2.73(m,1H),2.66-2.62(m,1H),2.32(m,2H),2.07(m,1H),1.87(m,3H).LC-MS:(ES+)＝494.4[M+H]+
Example 18.4- (2, 6-bis (benzyloxy) pyridin-3-yl) -8-bromopyrrolo [2,3,4-de ] quinolin-5 (4H) -one (compound 40):
step 1 Synthesis of N- (8-bromoquinolin-4-yl) picolinamide to a stirred suspension of 8-bromoquinolin-4-amine (CAS: 65340-75-2) in DMF (10 vol eq) was added picolinic acid (1 eq), TEA (3 eq) then HATU (1.1 eq) and the mixture stirred at room temperature. After completion of the reaction, the mixture is quenched, worked up and purified using standard protocols to give N- (8-bromoquinolin-4-yl) picolinamide.
Step 2, synthesizing 8-bromopyrrolo [2,3,4-de ]]Quinolin-5 (4H) -one N- (8-bromoquinolin-4-yl) picolinamide (1 eq), coCl 2 (0.3eq)、Ag 2 CO 3 (2.5 eq), benzene-1, 3, 5-tristricarboxylic acid ester (TFBen, 1.75 eq), pivOH (1 eq) and TEA (3 eq) in 1, 4-dioxane (10 vol eq) were heated at 130℃for 20 hours according to the procedure from Org. Lett.2019,21, 5694-5698. After completion of the reaction, the mixture was worked up and purified using standard protocols to give 8-bromopyrrolo [2,3,4-de ] ]Quinolin-5 (4H) -one.
Step 3 Synthesis of 3- (8-bromo-5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione NaH (5 eq) was added to a stirred solution of 8-bromopyrrolo [2,3,4-de ] quinolin-5 (4H) -one in THF (10 vol eq) at 0deg.C. The reaction mixture was stirred at this temperature for 15 minutes, then 3-bromopiperidine-2, 6-dione (1 eq) was added. The reaction mixture was slowly heated to 60 ℃ and stirred at that temperature until the reaction was complete. Standard work-up and purification provided 3- (8-bromo-5-oxo-pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione.
Step 4 Synthesis of 4- (2, 6-bis (benzyloxy) pyridin-3-yl) -8-bromopyrrolo [2,3,4-de ] quinolin-5 (4H) -one (Compound 40) in a sealed tube, 3-bromopyridine (1 eq) was combined with 8-bromopyrrolo [2,3,4-de ] quinolin-5 (4H) -one (1 eq), cuprous iodide (I) (0.1 eq), potassium carbonate (2 eq) and N, N' -dimethylethylenediamine (0.2 eq) according to the procedure from Aebi, J.et al (2013) and PCT application number WO 2013079452. The reaction mixture was heated at 110 ℃ overnight or until the reaction was complete. Standard workup and purification afforded 4- (2, 6-bis (benzyloxy) pyridin-3-yl) -8-bromopyrrolo [2,3,4-de ] quinolin-5 (4H) -one.
Example 19.3- (5-oxo-8- ((S) -2-oxoindolin-3-yl) pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 43A) and 3- (5-oxo-8- ((R) -2-oxoindolin-3-yl) pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 43B):
Step 1 Synthesis of 3- (8- (1H-indol-3-yl) -5-oxo-pyrrolo [2,3, 4-de)]Quinoline-4 (5H) -yl) piperidine-2, 6-dione (Compound 42) according to Lokhande et al (Advanced Synthesis)&1H-indole-3-carboxylic acid (1 eq), 3- (8-bromo-5-oxopyrrolo [2,3, 4-de) stirred and degassed in a similar manner as described in Catalysis,362 (14), 2857-2863)]Quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 40) (1.0 eq), K 3 PO 4 (2 eq.) palladium, di- μ -chlorobis [ (1, 2,3- η) -1-phenyl-2-propen-1-yl]A solution of di- (0.2 eq.) and L-aspartic acid (1.0 eq.) in THF (0.2M) was sealed and stirred at 100deg.C for 24 hours. After completion of the reaction, the reaction was concentrated and purified by column chromatography (DCM, meOH) to afford 3- (8- (1H-indole)-3-yl) -5-oxo-pyrrolo [2,3,4-de]Quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 42).
Step 2 Synthesis of 3- (5-oxo-8- ((S) -2-oxoindolin-3-yl) pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (Compound 43A) and 3- (5-oxo-8- ((R) -2-oxoindolin-3-yl) pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (Compound 43B) 3- (8- (1H-indol-3-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (Compound 42) (1.0 mmol) were dissolved in dimethyl sulfoxide (10 equivalents). Concentrated hydrochloric acid (12 n,18 eq.) was added dropwise to the reaction mixture at room temperature. After the reaction was completed, the reaction mixture was neutralized to pH >6. Concentrated ammonium hydroxide was added to the reaction mixture. The reaction mixture was extracted with dichloromethane. The organic phases are combined. The organic phase was dried over sodium sulfate, filtered and concentrated and purified by chiral SFC to give 3- (5-oxo-8- ((S) -2-oxoindolin-3-yl) pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 43A) and 3- (5-oxo-8- ((R) -2-oxoindolin-3-yl) pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 43B).
Example 20.3- (5-oxo-8- ((S) -1,2,3, 4-tetrahydroisoquinolin-3-yl) pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 44):
step 1 Synthesis of 8-vinylpyrpyrrolo [2,3,4-de ] quinolin-5 (4H) -one A stirred solution of 8-bromopyrrolo [2,3,4-de ] quinolin-5 (4H) -one (179.348 mmol) in toluene (800 mL) was purged with argon for 20 minutes, followed by the addition of tributylvinyltin (55.037 mL,188.315 mmol), triphenylphosphine (2.352 g,8.967 mmol) and tetrakis (triphenylphosphine) palladium (10.363 g,8.967 mmol). The reaction mixture was heated at 110℃for 16 hours. After completion of the reaction (monitored by TLC), the solution was evaporated under reduced pressure and the crude residue was purified by column chromatography (100-200 silica; gradient: 0-20% EtOAc/hexanes) to give 8-vinylpyr-o [2,3,4-de ] quinolin-5 (4H) -one.
Step 2 Synthesis of 5-oxo-4, 5-dihydropyrrolo [2,3,4-de ] quinoline-8-carbaldehyde to a stirred solution of 8-vinylpyr-ro [2,3,4-de ] quinolin-5 (4H) -one (112.5 mmol) in water (100 mL) and THF (300 mL) was added 4% aqueous solution of osmium tetroxide (578mg, 507.35. Mu. Mol,14.3 mL) and the reaction stirred at room temperature for 20 min. Sodium periodate (60.157 g,281.25 mmol) was added and the reaction stirred at room temperature for 1 hour. After the reaction was complete (monitored by TLC), the solution was filtered through celite bed and washed with THF and EtOAc. The organics were dried over sodium sulfate and concentrated under reduced pressure to give 5-oxo-4, 5-dihydropyrrolo [2,3,4-de ] quinoline-8-carbaldehyde X.
Step 3 Synthesis of (E) -2-methyl-N- ((5-oxo-4, 5-dihydropyrrolo [2,3, 4-de)]Quinolin-8-yl) methylene-propane-2-sulfinamide 2-methyl-2-propane sulfinamide (61 mg,0.5 mmol), 5-oxo-4, 5-dihydropyrrolo [2,3,4-de ]]A mixture of quinoline-8-carbaldehyde (0.5 mmol) and elemental iodine (13 mg,0.05 mmol) was placed in a 5mL milling cylinder. The reaction mixture was milled for 20 minutes at 30 Hz. The reaction mixture was dissolved in dichloromethane (20 mL). The reaction mixture was taken up in saturated Na 2 S 2 O 8 The solution (10 mL) was washed with brine (10 mL). The organic phase was dried over anhydrous MgSO 4 And (5) drying. The reaction mixture was filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (EtOAc/N-hexane) to give (E) -2-methyl-N- ((5-oxo-4, 5-dihydropyrrolo [2,3, 4-de)]Quinolin-8-yl) methylene) propane-2-sulfinamide.
Step 4 Synthesis of N- ((S) -2- (2- (hydroxymethyl) phenyl) -1- (5-oxo-4, 5-dihydropyrrolo [2,3, 4-de)]Quinolin-8-yl) ethyl) -2-methylpropan-2-sulfinamide A solution of phtalan (360 mg) was added dropwise to a blue suspension of lithium powder (140 mg,20.0 mmol) and a catalytic amount of DTBB (80.0 mg,0.3 mmol) in THF (5 mL) under argon. The mixture was stirred at 0℃for 45 min. Excess lithium was filtered off (through the cannula under argon and using a filter plate). ZnMe 2 (3.0 mL, 1.0M/hexane) solution was added dropwise to the mixture. Stirring of the mixture was continued for 15 minutes at room temperature. The reaction mixture was cooled to-65 ℃. N- ((S) -2- (2- (hydroxymethyl) phenyl) -1- (5-oxo-4, 5-dihydropyrrolo [2,3, 4-de)]Quinoline-8-yl) ethyl) -2-methylpropan-2-sulfinamide (1.0 mmol) in THF (0.4 mL)The liquid was added drop-wise to the mixture. After 12 hours, the reaction mixture was hydrolyzed with water (5 mL) at-65 ℃. The mixture was extracted with ethyl acetate (3X 15 mL) at room temperature. With anhydrous MgSO 4 The mixture was dried. The mixture was evaporated (15 Torr). The residue was purified by column chromatography (silica gel, hexane/ethyl acetate) to give N- ((S) -2- (2- (hydroxymethyl) phenyl) -1- (5-oxo-4, 5-dihydropyrrolo [2,3, 4-de)]Quinolin-8-yl) ethyl) -2-methylpropan-2-sulfinamide.
Step 5 Synthesis of (S) -8- (1, 2,3, 4-tetrahydroisoquinolin-3-yl) pyrrolo [2,3,4-de]Quinolin-5 (4H) -one A solution of 4M HCl (I mL) in dioxane was added to stirring N- ((S) -2- (2- (hydroxymethyl) phenyl) -1- (5-oxo-4, 5-dihydropyrrolo [2,3, 4-de) at 0deg.C]Quinolin-8-yl) ethyl) -2-methylpropan-2-sulfinamide (0.50 mmol) in MeOH (6 mL). The mixture was stirred at 0℃for 3 hours. Saturated NaHCO was added to the mixture 3 A solution. The reaction mixture was extracted with ethyl acetate (3X 10 mL). With anhydrous MgSO 4 The mixture was dried. The mixture was evaporated (15 Torr). The residue was dissolved in chloroform (5 mL). Thionyl chloride (1.7 mmol) was added to the mixture at 0deg.C. The solution was stirred at 50℃for 4 hours. The solvent was evaporated (15 Torr). The resulting residue was dissolved in THF (5 mL). To the mixture was added 5M sodium hydroxide solution (10 mL). The resulting mixture was vigorously stirred at 20℃for 10 hours. With anhydrous MgSO 4 The mixture was dried. The mixture was evaporated (15 Torr). Purification of the residue by column chromatography (silica gel, chloroform/methanol) to give (S) -8- (1, 2,3, 4-tetrahydroisoquinolin-3-yl) pyrrolo [2,3,4-de]Quinolin-5 (4H) -one.
Step 6 Synthesis of (S) -3- (5-oxo-4, 5-dihydropyrrolo [2,3, 4-de)]Quinolin-8-yl) -3, 4-dihydroisoquinolin-2 (1H) -carboxylic acid tert-butyl ester (S) -8- (1, 2,3, 4-tetrahydroisoquinolin-3-yl) pyrrolo [2,3,4-de ] at room temperature with stirring over 10 minutes]A solution of quinolin-5 (4H) -one (5.25 mmol) in dioxane (50 mL) was added dropwise di-tert-butyl dicarbonate (114.68 mg, 525.45. Mu. Mol, 120.59. Mu.L). The reaction mixture was stirred at room temperature for a further 5 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to give a crude residue, which was then dissolved in DCM and extracted with water. The organic solvent is treated by anhydrous Na 2 SO 4 Drying, filtering andconcentrating under reduced pressure at 50deg.C to obtain crude (S) -3- (5-oxo-4, 5-dihydropyrrolo [2,3, 4-de)]Quinolin-8-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylic acid tert-butyl ester is dried sufficiently to be used in the next step without further purification.
Step 7 Synthesis of 3- (5-oxo-8- ((S) -1,2,3, 4-tetrahydroisoquinolin-3-yl) pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (Compound 44) to a solution of tert-butyl (S) -3- (5-oxo-4, 5-dihydropyrrolo [2,3,4-de ] quinolin-8-yl) -3, 4-dihydroisoquinoline-2 (1H) -carboxylate (1 eq) in THF (10 vol eq) NaH (60%, 5eq in mineral oil) at this temperature and stirring the reaction at this temperature for 15 minutes followed by the addition of 3-bromopiperidine-2, 6-dione (1 eq). The reaction mixture was slowly heated to 60 ℃ and stirred at that temperature until the reaction was complete. Standard work-up and purification will afford tert-butyl ((3S) -3- (4- (2, 6-dioxopiperidin-3-yl) -5-oxo-4, 5-dihydropyrrolo [2,3,4-de ] quinolin-8-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) carboxylate. To a stirred solution of tert-butyl ((3S) -3- (4- (2, 6-dioxopiperidin-3-yl) -5-oxo-4, 5-dihydropyrrolo [2,3,4-de ] quinolin-8-yl) -3, 4-dihydroisoquinolin-2 (1H) -yl) carboxylate (7.33 mmol) in DCM (10 mL) was added a solution of 4.0M hydrogen chloride in dioxane (7.33 mmol,20 mL) at 0 ℃ and the reaction stirred at room temperature for 3 hours. The reaction was monitored by LCMS. After completion of the reaction, the solvent was evaporated under vacuum to give the crude product. The crude product was washed with diethyl ether (50 mL) to give 3- (5-oxo-8- ((S) -1,2,3, 4-tetrahydroisoquinolin-3-yl) pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 44).
EXAMPLE 21.3- (5-oxo-8- ((R) -1,2,3, 4-tetrahydroisoquinolin-3-yl) pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (Compound 45)
Compound 45 can be prepared by a similar method to that described above for compound 44, using the opposite enantiomer of 2-methyl-2-propanesulfenamide in step 3.
Example 22.3- (6- ((1-Benzylazetidin-3-yl) methyl) -2-oxobenzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 49) and 3- (6- ((1-methylazetidin-3-yl) methyl) -2-oxobenzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 50):
step 1 Synthesis of 3- ((1- (2, 6-Dioxopiperidin-3-yl) -2-oxo-1, 2-dihydrobenzo [ cd)]Indol-6-yl) methyl) azetidine-1-carboxylic acid tert-butyl ester (compound 47) ((1- (tert-butoxycarbonyl) azetidin-3-yl) methyl) trifluoroborate (1.3 eq., 0.13 mmol) and Cata CXium A Pd G3 (5 mol%,3.6mg,4.9x10-3 mmol) were weighed into a 4mL vial and purged with nitrogen. Addition of 3- (6-bromo-2-oxo-benzo [ cd)]An indole-1 (2H) -yl) piperidine-2, 6-dione (compound 1) (1 eq, 0.10 mmol) in 0.45mL of toluene. Cs with nitrogen bubbling 2 CO 3 Solution (3 eq, 7M in H) 2 In O, 43. Mu.L) and the reaction was stirred at 100℃for 72 hours. After completion, the reaction was concentrated, taken up in 1:1 methanol/DMSO and filtered through celite. Purification of the product by reverse phase HPLC gives 3- ((1- (2, 6-dioxopiperidin-3-yl) -2-oxo-1, 2-dihydrobenzo [ cd) ]Indol-6-yl) methyl-azetidine-1-carboxylic acid tert-butyl ester (compound 47).
Step 2 Synthesis of 3- (6- (azetidin-3-ylmethyl) -2-oxobenzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 48) to a stirred solution of 3- ((1- (2, 6-dioxopiperidin-3-yl) -2-oxo-1, 2-dihydrobenzo [ cd ] indol-6-yl) methyl) azetidine-1-carboxylate (compound 47) (7.33 mmol) in DCM (10 mL) at 0℃was added a solution of 4.0M hydrogen chloride in dioxane (7.33 mmol,20 mL) and the reaction was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. After the reaction was completed, the solvent was evaporated under vacuum to give a crude material. The crude product was washed with diethyl ether (50 mL) to give 3- (6- (azetidin-3-ylmethyl) -2-oxo-benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 48).
Step 3 Synthesis of 3- (6- ((1-Benzylazetidin-3-yl) methyl) -2-oxobenzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (Compound 49) to a stirred solution of 3- (6- (azetidin-3-ylmethyl) -2-oxobenzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (Compound 48) in THF (2 mL) was added benzaldehyde (15.92 mg, 150.05. Mu. Mol) and the solution was stirred for 10 min. Triethylamine (30.37 mg, 300.10. Mu. Mol, 41.83. Mu.L) was added to the solution, and the reaction mixture was stirred at room temperature for 30 minutes. Next, sodium cyanoborohydride (23.57 mg, 375.12. Mu. Mol) was added and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC, and after the reaction was completed, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 1-5% meoh in DCM and then purified by preparative HPLC to give 3- (6- ((1-benzyl azetidin-3-yl) methyl) -2-oxo-benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione as a yellow solid.
Step 4 Synthesis of 3- (6- ((1-methylazetidin-3-yl) methyl) -2-oxobenzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (Compound 50) to a stirred solution of 3- (6- (azetidin-3-ylmethyl) -2-oxobenzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (Compound 48) in THF (2 mL) was added paraformaldehyde (150.05. Mu. Mol) and the solution stirred for 10 min. Triethylamine (30.37 mg, 300.10. Mu. Mol, 41.83. Mu.L) was added to the solution, and the reaction mixture was stirred at room temperature for 30 minutes. Next, sodium cyanoborohydride (23.57 mg, 375.12. Mu. Mol) was added and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC, and after completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 1-5% meoh in DCM and then purified by preparative HPLC to give 3- (6- ((1-methylazetidin-3-yl) methyl) -2-oxobenzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 50) as a yellow solid.
Example 23.3- (8- ((1-Benzylazetidin-3-yl) methyl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 51):
Compound 51 can be prepared by the procedure used for compound 49 using 3- (8-bromo-5-oxo-pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione in step 1.
Example 24.3- (8- ((1-methylazetidin-3-yl) methyl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 52):
compound 52 can be prepared by the procedure used for compound 50 using 3- (8-bromo-5-oxo-pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione in step 1.
Example 25.3- (8- (3-benzyl-3-azabicyclo [3.1.0] hex-6-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 56) and 3- (8- (3-methyl-3-azabicyclo [3.1.0] hex-6-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 57):
step 1 Synthesis of 6- (4- (2, 6-dioxopiperidin-3-yl) -5-oxo-4, 5-dihydropyrrolo [2,3, 4-de)]Quinolin-8-yl) -3-azabicyclo [3.1.0]Hexane-3-carboxylic acid ester (Compound 54) corresponding (3- (tert-butoxycarbonyl) -3-azabicyclo [ 3.1.0) was added to a sealed test tube under argon atmosphere]Hexahex-6-yl) trifluoroborate (Compound 40) (0.503 mmol,1.2 eq. Synthesized from 1H-pyrrole-1-carboxylic acid, 2, 5-dihydro-, 1-dimethylethyl ester, 3- (8-bromo-5-oxopyrrolo [2,3, 4-de) by the method of Charette et al (Synlett, (11) 1779-1782; 2005) ]Quinolin-4 (5H) -yl) piperidine-2, 6-dione (0.419 mmol,1.0 eq.) K 3 PO 4 (295 mg,1.385mmol,3.3 eq.) Pd (OAc) 2 (2.8 mg,0.013mmol,0.03 eq.) 2-diphenyldicyclohexylphosphine (8.8 mg,0.027mmol,0.06 eq.) and 1.7mL toluene-H 2 O (3:1 v/v). The reaction mixture was stirred at 100℃for 20 hours. The reaction was cooled to room temperature and quenched by addition of water. The mixture was then transferred to a flask containing Et 2 The extraction funnel of O and the organic phase was removed. Et for aqueous phase 2 O (2X 15 mL) extraction and combining the organic phases with Na 2 SO 4 Dried, filtered and concentrated under reduced pressure. Purification of the crude cyclopropane by flash chromatography (EtOAc-hexanes) afforded the corresponding 6- (4- (2, 6-dioxopiperidin-3-yl) -5-oxo-4, 5-dihydropyrrolo [2,3, 4-de)]Quinolin-8-yl) -3-azabicyclo [3.1.0]Hexane-3-carboxylic acid tert-butyl ester (compound 54).
Step 2 Synthesis of 3- (8- (3-azabicyclo [3.1.0] hex-6-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 55) to a stirred solution of 6- (4- (2, 6-dioxopiperidin-3-yl) -5-oxo-4, 5-dihydropyrrolo [2,3,4-de ] quinolin-8-yl) -3-azabicyclo [3.1.0] hexane-3-carboxylic acid tert-butyl ester (compound 54) (7.33 mmol) in DCM (10 mL) at 0deg.C was added a solution of 4.0M hydrogen chloride in dioxane (7.33 mmol,20 mL) and the reaction was stirred at room temperature for 3 hours. The reaction was monitored by LCMS. After the reaction was completed, the solvent was evaporated under vacuum to give a crude product. The crude product was washed with diethyl ether (50 mL) to give 3- (8- (3-azabicyclo [3.1.0] hex-6-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 55).
Step 3 Synthesis of 3- (8- (3-benzyl-3-azabicyclo [3.1.0] hex-6-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (Compound 56) to a stirred solution of 3- (8- (3-azabicyclo [3.1.0] hex-6-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (Compound 55) in THF (2 mL) was added benzaldehyde (15.92 mg, 150.05. Mu. Mol) and the solution was stirred for 10 minutes. Triethylamine (30.37 mg, 300.10. Mu. Mol, 41.83. Mu.L) was added to the solution, and the reaction mixture was stirred at room temperature for 30 minutes. Next, sodium cyanoborohydride (23.57 mg, 375.12. Mu. Mol) was added and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC, and after completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 1-5% meoh in DCM followed by preparative HPLC to give 3- (8- (3-benzyl-3-azabicyclo [3.1.0] hex-6-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 56) as a yellow solid.
Step 4 Synthesis of 3- (8- (3-methyl-3-azabicyclo [3.1.0] hex-6-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (Compound 57) to a stirred solution of 3- (8- (3-azabicyclo [3.1.0] hex-6-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (Compound 55) in THF (2 mL) was added paraformaldehyde (150.05. Mu. Mol) and the solution was stirred for 10 minutes. Triethylamine (30.37 mg, 300.10. Mu. Mol, 41.83. Mu.L) was added to the solution, and the reaction mixture was stirred at room temperature for 30 minutes. Next, sodium cyanoborohydride (23.57 mg, 375.12. Mu. Mol) was added and the reaction mixture was stirred at room temperature for 16 hours. The progress of the reaction was monitored by TLC, and after the reaction was completed, the reaction mixture was diluted with ethyl acetate and washed with water and brine. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude compound was purified by column chromatography eluting with 1-5% meoh in DCM followed by preparative HPLC to give 3- (8- (3-methyl-3-azabicyclo [3.1.0] hex-6-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 57) as a yellow solid.
Example 26.3- (5- (3-benzyl-3-azabicyclo [3.1.0] hex-6-yl) -2-oxo-benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 58):
compound 58 can be prepared from the procedure used for compound 56 using 3- (6-bromo-2-oxo-benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione in step 1.
EXAMPLE 27.3- (5- (3-methyl-3-azabicyclo [3.1.0] hex-6-yl) -2-oxo-benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione
Compound 59 can be prepared from the procedure used for compound 57 using 3- (6-bromo-2-oxo-benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione in step 1.
Example 28.3- (8- (1-Benzylpiperidin-4-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 60):
potassium (1-benzylpiperidin-4-yl) trifluoroborate (1.2 eq), aryl bromide (1.0 eq), K were added to a sealed tube under argon atmosphere 3 PO 4 (3.3eq)、Pd(OAc) 2 (0.03 eq), 2-diphenyldicyclohexylphosphine (0.06 eq) (Compound 40) and toluene/H 2 O (3:1 v/v, 0.1M). The reaction mixture was stirred at 100℃for 20 hours. The reaction was cooled to room temperature and quenched by addition of water. The mixture was then taken up in Et 2 O (x 3) extraction, then the combined organic layers were washed with brine (x 1) and dried over sodium sulfate, then filtered and concentrated to a crude residue. The crude material was then purified using flash column chromatography to give the product 3- (8- (1-benzylpiperidin-4-yl) -5-oxopyrrolo [2,3, 4-de) ]Quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 60).
Compound 61-compound 71 was prepared using the same procedure as described for the preparation of 3- (8- (1-benzylpiperidin-4-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 60) described in example 28, using the appropriate starting materials in the table.
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Compound 72-compound 75 was prepared using the same procedure described for the preparation of 3- (2-oxo-5- ((S) -2-phenylpyrrolidin-1-yl) benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 18) described in example 7, using the appropriate amine starting material from the table.
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Example 29.3- (5- (((trans) -2- (3- (3-fluorophenoxy) azetidin-1-yl) cyclohexyl) oxy) -2-oxo-benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 76):
step 1 3- (3-fluorophenoxy) azetidine-1-carboxylic acid tert-butyl ester to a cooled (0 ℃) solution of 3-fluorophenol (1 eq) in THF (0.1M) NaH (2 eq, 60% dispersion in mineral oil) was added in portions, then a solution of 3-bromoazetidine-1-carboxylic acid ester (1 eq in THF) was added dropwise to the reaction mixture. The mixture was then stirred while monitored by LCMS/TLC. After the reaction was completed, the mixture was cooled to 0 ℃ and quenched with water. Standard work-up and purification procedures will provide the product tert-butyl 3- (3-fluorophenoxy) azetidine-1-carboxylate.
Step 2 3- (3-fluorophenoxy) azetidine hydrochloride 3- (3-fluorophenoxy) azetidine-1-carboxylic acid ester (1 eq) was suspended in HCl (4M in 1, 4-dioxane, 20 eq) and stirred at room temperature, monitored by LCMS/TLC. After the reaction was completed, the mixture was concentrated to dryness to 3- (3-fluorophenoxy) azetidine hydrochloride, which was used without further purification.
Step 3 (trans) -2- (3- (3-fluorophenoxy) azetidin-1-yl) cyclohex-1-ol 3- (3-fluorophenoxy) azetidine hydrochloride (1 eq) was suspended in DMSO (0.1M) and then K was added in portions 2 CO 3 (3 eq). Then 7-Oxabicyclo [4.1.0]Heptane (1 eq) and the suspension was heated to 100 ℃ until the starting material was consumed. After the reaction was completed, the mixture was cooled to room temperature and taken up with H 2 And O quenching. Standard work-up and purification procedures give the product (trans) -2- (3- (3-fluorophenoxy) azetidin-1-yl) cyclohex-1-ol.
Step 4 3- (5- (((trans) -2- (3- (3-fluorophenoxy) azetidin-1-yl) cyclohexyl) oxy) -2-oxo-benzo [ cd)]Indole-1 (2H) -yl) piperidine-2, 6-dione (compound 76) DIPEA (3 eq) was added to a suspension of (trans) -2- (3- (3-fluorophenoxy) azetidin-1-yl) cyclohex-1-ol (1 eq) in DMSO (0.1M), followed by compound 17 (1 eq). The reaction mixture was heated to 100 ℃ with stirring until TLC/LCMS indicated the starting material was consumed. After the reaction was completed, the mixture was cooled to room temperature and taken up with H 2 And O quenching. Standard work-up and purification procedures give the product 3- (5- (((trans) -2- (3- (3-fluorophenoxy) azetidin-1-yl) cyclohexyl) oxy) -2-oxo-benzo [ cd)]Indol-1 (2H) -yl) piperidine-2, 6-dione (compound 76).
Example 30.3- (8- (((trans) -2- (3- (3-fluorophenoxy) azetidin-1-yl) cyclohexyl) oxy) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 77):
3- (8-bromo-5-oxo-pyrrolo [2,3, 4-de) under argon atmosphere as described by Chen et al (J.am.chem. Soc.2019,141, 3541-3549)]Quinoline-4 (5H) -yl) piperidine-2, 6-dione (Compound 40) (1 eq), cuI (0.01 eq), t-Buona (1.2 eq), DPEO (0.01 eq), (trans) -2- (3- (3-fluorophenoxy) azetidin-1-yl) cyclohex-1-ol (1 eq),MS (400-500 mg/5mmol SM) was suspended in 1, 4-dioxane (2M). The mixture was then heated to 80 ℃ with vigorous stirring for 24 hours. After the reaction was completed, the mixture was cooled to room temperature and was treated with NH 4 Cl (aq) was acidified, then diluted with EtOAc and extracted (x 3). The combined organic layers were washed with brine (×1) anddried over sodium sulfate, then filtered and concentrated to a crude residue which is purified using standard column chromatography to give 3- (8- (((trans) -2- (3- (3-fluorophenoxy) azetidin-1-yl) cyclohexyl) oxy) -5-oxopyrrolo [2,3, 4-de) ]Quinolin-4 (5H) -yl) piperidine-2, 6-dione.
Example 31.4- (2, 6-Dioxopiperidin-3-yl) -5-oxo-N- ((3R, 5S) -1,3, 5-trimethylpiperidin-4-yl) -4, 5-dihydropyrrolo [2,3,4-de ] quinoline-8-carboxamide (compound 78):
step 1 5-oxo-4, 5-dihydropyrrolo [2,3,4-de ]]Quinoline-8-carboxylic acid to cooled (-78 ℃ C.) 8-bromopyrrolo [2,3,4-de ]]Et of quinolin-5 (4H) -one (1 eq) 2 O (0.1M) solution was added (n-BuLi solution, 3 eq) and the mixture was stirred for 30 minutes. CO is then subjected to 2 The gas was introduced into the solution (dry ice effluent dried by a calcium chloride plug) and the reaction was monitored until the starting material was consumed. After the reaction was completed, the solution was slowly warmed to room temperature and then carefully treated with NH 4 The aqueous Cl solution was quenched. Standard work-up and purification procedures will give 5-oxo-4, 5-dihydropyrrolo [2,3,4-de ]]Quinoline-8-carboxylic acid as product.
Step 2 4- (2, 6-Dioxopiperidin-3-yl) -5-oxo-N- ((3R, 5S) -1,3, 5-trimethylpiperidin-4-yl) -4, 5-dihydropyrrolo [2,3,4-de]Quinoline-8-carboxamide 5-oxo-4, 5-dihydropyrrolo [2,3,4-de ] at room temperature]To a solution of quinoline-8-carboxylic acid (1 eq) in DMF (0.1M) was added (3R, 5S) -1,3, 5-trimethylpiperidin-4-amine (1 eq), DIPEA (2 eq) and HATU (1 eq). The reaction was then monitored by TLC/LCMS and, after completion of the reaction, by addition of H 2 The mixture was quenched with O. Standard work-up and purification procedures will give 4- (2, 6-dioxopiperidin-3-yl) -5-oxo-N- ((3R, 5S) -1,3, 5-trimethylpiperidin-4-yl) -4, 5-dihydropyrrolo [2,3,4-de]Quinoline-8-carboxamide as product.
Step 3 4- (2, 6-Dioxopiperidin-3-yl) -5-oxo-N- ((3R, 5S) -1,3, 5-trimethylpiperidin-4-yl) -4, 5-dihydropyrrolo [2,3,4-de ] quinoline-8-carboxamide (compound 78) to a solution of 4- (2, 6-dioxopiperidin-3-yl) -5-oxo-N- ((3R, 5S) -1,3, 5-trimethylpiperidin-4-yl) -4, 5-dihydropyrrolo [2,3,4-de ] quinoline-8-carboxamide (1 eq) in THF (0.1M) was added in portions after the addition was completed, the resulting mixture was warmed to room temperature, 3-bromopiperidin-2, 6-dione (5 eq) was added and then stirred at 70℃until the starting material was consumed after the reaction was completed, the mixture was treated with crushed ice and the post-treatment mixture was quenched by addition to give as a standard product of 3- (2, 6-dioxopiperidin-3, 5-yl) -4, 5-dihydro-pyrrolo [2,3,4-de ] quinoline-8-carboxamide (1 eq).
Compound 79 was prepared using the same procedure as described in example 31 for the preparation of 4- (2, 6-dioxopiperidin-3-yl) -5-oxo-N- ((3 r,5 s) -1,3, 5-trimethylpiperidin-4-yl) -4, 5-dihydropyrrolo [2,3,4-de ] quinoline-8-carboxamide (compound 78) using the appropriate amine starting material from this table.
Example 32.3- (8-fluoro-5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 80):
as described in the procedure of Sather et al (J.am.chem. Soc.2015,137, 13433-13438), 3- (8-bromo-5-oxopyrrolo [2,3, 4-de) was reacted under an inert atmosphere]To a toluene (0.1M) solution of quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 40) (1 eq) was added CsF (3 eq) and [ (AlPhosPd) 2 ●COD](0.01 eq). The mixture was then stirred at room temperature until the reaction was complete. After the reaction was completed, the mixture was filtered through a celite pad. The crude filtrate was concentrated to a residue which was purified using standard flash chromatography to give 3- (8-fluoro-5-oxo-pyrrolo [2,3, 4-de)]Quinoline-4 (5H) -yl) piperidine-2, 6-dione (compound 80) as a product.
Compound 81-compound 82 was prepared using the same procedure as described in example 32 for the preparation of 3- (2-oxo-5- ((S) -2-phenylpyrrolidin-1-yl) benzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 18) using 3- (8-fluoro-5-oxo-pyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 80) and the appropriate amine starting material from the table.
Example 33.3- (5- (1-benzyl-4-methylpiperidin-4-yl) -2-oxobenzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 83):
Step 1 (1-benzyl-4-methylpiperidin-4-yl) potassium trifluoroborate 1-benzyl-4-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) piperidine was prepared according to the procedure reported by Friese et al, angew.chem.int.Ed.2019,58,9561-9564 and converted to potassium (1-benzyl-4-methylpiperidin-4-yl) trifluoroborate according to the standard procedure reported by Lennox et al, angew.int.Ed.2012, 51, 9385-9388.
Step 2 3- (5- (1-benzyl-4-methylpiperidin-4-yl) -2-oxobenzo [ cd)]Indole-1 (2H) -yl) piperidine-2, 6-dione (1 eq) Potassium (1-benzyl-4-methylpiperidin-4-yl) trifluoroborate, pd (dppf) Cl 2 (0.1eq)、Ag 2 A solution of O (2 eq) and compound 1 (1 eq) in toluene (0.1M) was heated at 100℃under an inert atmosphere. The reaction was monitored by TLC/LCMS and after consumption of the starting material the mixture was diluted with EtOAc and filtered through a celite pad. Standard work-up and purification procedures will afford 3- (5- (1-benzyl-4-methylpiperidin-4-yl) -2-oxo-benzo [ cd)]Indole-1 (2H) -yl) piperidine-2, 6-dione (compound 83) was used as a product.
Using the same procedure as described for the preparation of 3- (5- (1-benzyl-4-methylpiperidin-4-yl) -2-oxobenzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 83) described in example 33, compound 84-compound 86 was prepared using the appropriate boronate ester and aryl bromide from the table.
Example 34.3- (5- (1-benzyl-4-fluoropiperidin-4-yl) -2-oxobenzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 87):
step 1 5-bromo-1- (4-methoxybenzyl) benzo [ cd ]]Indol-2 (1H) -ones are prepared by reacting 5-bromobenzo [ cd ] at room temperature]DIPEA (2 eq) was added to a solution of indol-2 (1H) -one (1 eq) in DMF (0.1M), followed by PMBCl (1.1 eq). The mixture was stirred while monitored by TLC/LCMS. After completion of the reaction, H was added 2 The mixture was quenched with O. Standard work-up and purification procedures will afford 5-bromo-1- (4-methoxybenzyl) benzo [ cd ]]Indol-2 (1H) -ones as products.
Step 2 5- (1-benzyl-4-hydroxypiperidin-4-yl) -1- (4-methoxybenzyl) benzo [ cd]Indol-2 (1H) -one to cooled (-78 ℃ C.) 5-bromo-1- (4-methoxybenzyl) benzo [ cd ]]BuLi (2 eq) was added dropwise to a solution of indol-2 (1H) -one (1 eq) in THF (0.1M), and the mixture was stirred for 30 minutes. 1-Benzylpiperidin-4-one (1 eq) was then added to the reaction mixture and stirring was continued at ambient temperature until the reaction was significantly completed. After the reaction was completed, the mixture was cooled to 0℃and then purified by adding H 2 O was carefully quenched. Standard work-up and purification procedures will give 5- (1-benzyl-4-hydroxypiperidin-4-yl) -1- (4-methoxybenzyl) benzo [ cd ] ]Indol-2 (1H) -ones as products.
Step 3 5- (1-benzyl-4-fluoropiperidin-4-yl) -1- (4-methoxybenzyl) benzo [ cd ] indol-2 (1H) -one DAST (1.5 eq) was added dropwise to a cooled (0 ℃) solution of 5- (1-benzyl-4-hydroxypiperidin-4-yl) -1- (4-methoxybenzyl) benzo [ cd ] indol-2 (1H) -one (1 eq) in DCM (0.1M). The reaction mixture was stirred at room temperature until the reaction was significantly completed. After the reaction was completed, the mixture was concentrated to dryness. Standard work-up and purification procedures will give 5- (1-benzyl-4-fluoropiperidin-4-yl) -1- (4-methoxybenzyl) benzo [ cd ] indol-2 (1H) -one as product.
Step 4 5- (1-benzyl-4-fluoropiperidin-4-yl) benzo [ cd ] indol-2 (1H) -one 5- (1-benzyl-4-fluoropiperidin-4-yl) -1- (4-methoxybenzyl) benzo [ cd ] indol-2 (1H) -one (1 eq) was suspended in TFA (0.1M) at room temperature, then triflic acid (5 eq) was added dropwise and the reaction mixture was heated to reflux until the starting material was consumed. After the reaction was completed, the mixture was cooled to room temperature and concentrated to dryness. Standard work-up and purification procedures will give 5- (1-benzyl-4-fluoropiperidin-4-yl) benzo [ cd ] indol-2 (1H) -one as a product.
Step 5 3- (5- (1-benzyl-4-fluoropiperidin-4-yl) -2-oxo-benzo [ cd)]Indol-1 (2H) -yl) piperidine-2, 6-dione (Compound 87) is prepared by cooling (0 ℃) 5- (1-benzyl-4-fluoropiperidin-4-yl) benzo [ cd ] ]To a solution of indol-2 (1H) -one (1 eq) in THF was added NaH (10 eq, 60% dispersion in mineral oil) in portions. The mixture was warmed to room temperature, followed by the addition of 3-bromopiperidine-2, 6-dione (5 eq) and then the mixture was heated to reflux until the reaction was significantly completed. After the reaction was completed, the mixture was cooled to 0℃and then carefully treated with H 2 And O quenching. Standard work-up and purification procedures will give 3- (5- (1-benzyl-4-fluoropiperidin-4-yl) -2-oxo-benzo [ cd)]Indole-1 (2H) -yl) piperidine-2, 6-dione as product.
Compound 88-compound 95 was prepared using the same procedure as described for the preparation of 3- (5- (1-benzyl-4-fluoropiperidin-4-yl) -2-oxobenzo [ cd ] indol-1 (2H) -yl) piperidine-2, 6-dione (compound 87) described in example 34, using the appropriate aryl bromide and ketone from the table.
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EXAMPLE 35 3- [5- (1-benzyl-4-fluoro-4-piperidinyl) -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 96)
Step 1, stirring 5-bromo-1H-benzo [ cd ] at-78deg.C under inert atmosphere]To a solution of indol-2-one (400 mg,1.61 mmol) in anhydrous THF (5.0 mL) was added 1.8M di-n-butyl ether solution of phenyl lithium (135.52 mg,1.61mmol, 167.30. Mu.L), and the reaction was stirred at the same temperature for 30 minutes, then butyl lithium (113.62 mg,1.77 mmol) was added at the same temperature. After the addition, the temperature was raised to-40 ℃ and the reaction mixture was stirred at the same temperature for 30 minutes. A solution of 1-benzylpiperidin-4-one (305.16 mg,1.61mmol, 287.88. Mu.L) in dry THF (5.0 mL) was then added at-78deg.C and the reaction mixture was warmed to room temperature and stirred for an additional 16 hours. After the reaction was completed, the reaction mixture was quenched with an ammonium chloride solution and diluted with ethyl acetate (50 mL). The combined organic layers were washed with water/brine and separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting crude product was purified by flash chromatography using 0-5% meoh-DCM to give 5- (1-benzyl-4-hydroxy-4-piperidinyl) -1H-benzo [ cd ] as a brown solid ]Indol-2-one (255 mg, 569.15. Mu. Mol,35% product). 1 H NMR(400MHz,DMSO-d 6 )δ10.68(s,1H),8.20(d,J＝8.84Hz,1H),7.93(d,J＝7.4Hz,1H),7.88(d,J＝7.44Hz,1H),7.44(t,J＝7.2Hz,1H),7.33-7.30(m,5H),6.93(d,J＝7.04Hz,1H),5.4(br m,1H),3.64(br,2H),2.74-2.66(br,4H),2.32(br m,2H),1.94-1.90(m,2H).
Step 2. 5- (1-benzyl-4-hydroxy-4-piperidinyl) -1H-benzo [ cd ] at-78deg.C under an inert atmosphere]To a solution of indol-2-one (150 mg, 418.49. Mu. Mol) in anhydrous DCM (15.0 mL) was added dropwise N-ethyl-N- (trifluoro- $l {4} -sulfanyl) ethylamine (337.28 mg,2.09mmol, 276.46. Mu.L) and the reaction mixture was stirred at room temperature for an additional 5 hours. After completion of the reaction, the reaction mixture was diluted with 10% meoh-DCM (20 mL) and quenched with saturated sodium bicarbonate solution. The organic phase was washed with water/brine and separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by flash column chromatography using 0-5% meoh-DCM to give 5- (1-benzyl-4-fluoro-4-piperidinyl) -1H-benzo [ cd ] as a brown gum]Indol-2-one (70 mg, 185.28. Mu. Mol,44% yield). LC-MS (ES) + ):m/z 361.39[M+H] + .
Step 3 to cooled 5- (1-benzyl-4-fluoro-4-piperidinyl) -1H-)Benzo [ cd ]]Sodium hydride (60% dispersion in mineral oil) (74.42 mg,1.94 mmol) was added portionwise to a solution of indol-2-one (70 mg, 194.22. Mu. Mol) in dry THF (5 mL) and the temperature maintained<5 ℃. After the addition, the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled again to 0deg.C and 3-bromopiperidine-2, 6-dione (186.46 mg, 971.08. Mu. Mol) was added in portions. The resulting solution was heated at 70℃for 1 hour. After completion, the reaction mixture was cooled to 0 ℃ and quenched by addition of ice-cold water (10 mL). The aqueous layer was extracted with ethyl acetate (3X 50 mL). The combined organics were separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give crude 3- [5- (1-benzyl-4-fluoro-4-piperidinyl) -2-oxo-benzo [ cd ] ]Indol-1-yl]Piperidine-2, 6-dione was purified by PREP TLC to give 3- [5- (1-benzyl-4-fluoro-4-piperidinyl) -2-oxo-benzo [ cd ] as a yellow solid]Indol-1-yl]Piperidine-2, 6-dione (compound 96,36mg, 74.00. Mu. Mol,38% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),8.07(d,J＝6.88Hz,1H),7.94(d,J＝8.28Hz,1H),7.88(d,J＝7.36Hz,1H),7.56(t,J＝7.52Hz,1H),7.37-7.33(m,4H),7.28-7.27(m,1H),7.17(d,J＝7.0Hz,1H),5.46-5.44(m,1H),3.60(s,2H),2.97-2.85(m,4H),2.77-2.63(m,3H),2.49-2.18(m,4H),2.09(m,1H)；LC-MS(ES + ):m/z 472.28[M+H] + .
3- [5- (4-fluoro-1-methyl-4-piperidinyl) -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (compound 97)
Compound 97 was prepared essentially following the synthesis of compound 96.
1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),8.08(d,J＝7.12Hz,1H),7.93(d,J＝8.76Hz,1H),7.87(d,J＝7.48Hz,1H),7.55(t,J＝7.24Hz,1H),7.17(d,J＝7.24Hz,1H),5.45(dd,J＝12.32,4.84Hz,1H),2.94-2.91(m,3H),2.79-2.49(m,3H),2.43-2.32(s,4H),2.28(s,3H),2.2-2.07(m,2H)；LC-MS(ES + ):m/z 396.37[M+H] + .
EXAMPLE 36 Synthesis of 5- (1-Chloropyrrolidin-3-yl) -1H-benzo [ cd ] indol-2-one
Step 1 in a flame dried 100mL two neck round bottom flask in N 2 Next, 5-bromo-1H-benzo [ cd ]]Indol-2-one (1 g,4.03 mmol) is dissolved in anhydrous THF (10.0 mL) and phenyl lithium (1.9M, 2.12 mL) in di-n-butyl ether is added at-78deg.C. The resulting solution was stirred at the same temperature for 30 minutes, followed by the addition of butyllithium (1.66M, 2.67 mL) at-78deg.C. After the addition was complete, the temperature was raised to-40 ℃ and the reaction mixture was stirred at the same temperature for an additional 30 minutes. A solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (746.63 mg,4.03 mmol) in dry THF (10.0 mL) was added at-78deg.C and the reaction mixture was allowed to warm to room temperature and stirred for an additional 16 hours. After the reaction was completed, the reaction mixture was quenched with ammonium chloride solution (20 mL) and extracted with ethyl acetate (40×2 mL). The combined organic layers were separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude reaction mass was purified by flash chromatography using 0-5% meoh-DCM to give 3-hydroxy-3- (2-oxo-1H-benzo [ cd) as a brown solid ]Indol-5-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (490.0 mg,1.10mmol,27% yield). LC-MS (ES) + ):m/z 299.17[M–tBu+H] + .
Step 2-3-hydroxy-3- (2-oxo-1H-benzo [ cd ] at 0deg.C]HPLC grade CHCl of tert-butyl indol-5-yl) pyrrolidine-1-carboxylate (3836 mg,1.09 mmol) 3 To a solution (10.0 mL) was added triethylamine, 99% (440.85 mg,4.36mmol, 607.23. Mu.L), followed by methanesulfonyl chloride (509.24 mg,4.36mmol, 344.08. Mu.L), and the resulting reaction mixture was refluxed at 80℃for 16 hours. After the reaction was complete, the reaction mixture was diluted with DCM (30 mL) and the organic layer was washed with saturated sodium bicarbonate solution, then water and brine solution. The combined organic phases were separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 3-chloro-3- (2-oxo-1H-benzo [ cd)]Indol-5-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg,1.07mmol,99% yield) was used directly in the next step without purification and characterization.
Step 3-crude 3-chloro-3- (2-oxo-1H-benzo [ cd) under stirring at room temperature]Indoles-To a solution of tert-butyl 5-yl-pyrrolidine-1-carboxylate (400 mg,1.07 mmol) in methanol (6.0 mL) was added ammonium formate 99% (676.53 mg,10.73mmol, 528.54. Mu.L), pd/C (45.62 mg, 375.66. Mu. Mol) and the resulting reaction mixture was heated in a sealed vial at 70℃for 4 hours. After completion of the reaction, the reaction mixture was filtered through a celite pad and washed with 10% meoh-DCM. The combined filtrates were then washed with cold water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound 3- (2-oxo-1H-benzo [ cd) ]Indol-5-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (360 mg, 531.92. Mu. Mol,50% yield) was used directly in the next step. LC-MS (ES) + ):m/z339.1[M+H] + .
Step 4-3- (2-oxo-1H-benzo [ cd) under stirring at 0deg.C]A solution of tert-butyl indol-5-yl) pyrrolidine-1-carboxylate (360.0 mg,1.06 mmol) in dioxane (2 mL) was added 4M dioxane-HCl (10 mL) and the resulting solution stirred at room temperature for an additional 2 hours. After completion of the reaction, volatiles were removed under reduced pressure, and the resulting solid was washed with diethyl ether and pentane to give 5- (1-chloropyrrolidin-3-yl) -1H-benzo [ cd ] as a brown solid]Indol-2-one hydrochloride (290.0 mg, 931.86. Mu. Mol,88% yield) was used in the next step without purification. LC-MS (ES) + ):m/z 239.1[M+H] + .
EXAMPLE 37 Synthesis of 3- [5- (1-methylpyrrolidin-3-yl) -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 98)
Step 1 5-pyrrolidin-3-yl-1H-benzo [ cd ] is placed in a dried 50ml round bottom flask]Indol-2-ones; hydrochloride (290 mg,1.06 mmol) and formaldehyde (31.69 mg,1.06mmol,29.35 μl) were dissolved in methanol (2.0 mL) -DCM (5.0 mL). To the solution were added triethylamine (106.81 mg,1.06mmol, 147.12. Mu.L) and acetic acid (126.77 mg,2.11mmol, and 120.73. Mu.L), and the resulting reaction mixture was stirred at room temperature for 5-6 hours. The reaction mixture was then cooled at 0 ℃; sodium triacetoxyborode (1.12 g,5.28 mmol) was added and stirring was continued at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated under reduced pressure and concentrated using 0-10% MeOH-DCM The crude compound was purified by flash column chromatography to give 8- (1-methylpyrrolidin-3-yl) -15, 16-diazatricyclododecane-1 (8), 2 (9), 3 (10), 4 (15), 11-pentaen-14-one (110 mg,269.25 μmol,26% yield) as a yellow solid. LC-MS (ES) + ):m/z 253.34[M+H] + .
Step 2 to cooled 5- (1-methylpyrrolidin-3-yl) -1H-benzo [ cd ]]Sodium hydride (60% dispersion in mineral oil) (417.62 mg,10.44 mmol) was added portionwise to a solution of indol-2-one (110 mg, 435.97. Mu. Mol) in anhydrous THF (5 mL) and the temperature was maintained<5 ℃. The resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was then cooled again to 0deg.C and 3-bromopiperidine-2, 6-dione (1.00 g,5.23 mmol) was added in portions. After the addition was completed, the resulting solution was heated at 70 ℃ for 1 hour. In 5- (1-methylpyrrolidin-3-yl) -1H-benzo [ cd ]]After complete exhaustion of indol-2-one, the reaction mixture was cooled to 0 ℃ and quenched by addition of ice-cold water (5 mL) and extracted with ethyl acetate (3×50 mL). The combined organics were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude reaction material was purified by PREP TLC to give 3- [5- (1-methylpyrrolidin-3-yl) -2-oxo-benzo [ cd ] as a yellow solid]Indol-1-yl]Piperidine-2, 6-dione (Compound 98,10.0mg, 26.00. Mu. Mol,6% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),8.05(d,J＝7.36Hz,1H),7.92(d,J＝8.68Hz,1H),7.83(d,J＝7.4Hz,1H),7.53(t,J＝7.68Hz,1H),7.14(d,J＝7.2Hz,1H),5.44(dd,J＝12.84,5.32Hz,1H),4.16(m,1H),2.96-2.62(m,6H),2.77-2.62(m,2H),2.32(s,3H),2.07(m,1H),1.90(m,1H).LC-MS(ES + ):m/z 364.25[M+H] + .
3- [5- (1-Benzylpyrrolidin-3-yl) -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 99)
Compound 99 was prepared essentially according to the synthesis of compound 98.
LC-MS(ES + ):m/z 440.3[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.10(s,1H),8.04(d,J＝7.32Hz,1H),7.95(d,J＝8.68Hz,1H),7.83(d,J＝7.36Hz,1H),7.52(t,J＝8.08Hz,1H),7.38(br d,J＝7.04Hz,2H),7.33(t,J＝7.28Hz,2H),7.26-7.24(m,1H),7.13(d,J＝7.16Hz,1H),5.44(dd,J＝12.84,5.32Hz,1H),4.16(m,1H),3.72-3.69(br m,2H),2.96-2.89(m,5H),2.8-2.73(m,2H),2.49-2.44(m,1H),2.09-2.06(m,1H),1.94-1.90(m,1H).
EXAMPLE 38 Synthesis of 5- (3-hydroxyazetidin-3-yl) -1H-benzo [ cd ] indol-2-one
Step 1 in a flame dried two neck round bottom flask in N 2 5-bromo-1H-benzo [ cd ] under an atmosphere]Indol-2-one (1.0 g,4.03 mmol) is dissolved in dry THF (5.0 mL) and cooled at-78deg.C. To this cooled solution was added a di-n-butyl ether solution of phenyl lithium (1.8 m,2.24 ml), and the reaction was stirred at the same temperature for 30 minutes, then butyl lithium (1.62 m,2.74 ml) was added at the same temperature. After the addition, the temperature was raised to-40 ℃ and the reaction mixture was stirred at the same temperature for 30 minutes. A solution of tert-butyl 3-oxetane-1-carboxylate (690.09 mg,4.03mmol, 287.88. Mu.L) in anhydrous THF (5.0 mL) was added at-78deg.C, and the reaction mixture was allowed to warm at room temperature and stirred for an additional 16 hours. After formation of a new spot as confirmed by TLC, the reaction mixture was quenched with ammonium chloride solution and diluted with ethyl acetate (100 mL). The combined organic layers were washed with water/brine and separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was then purified by flash column chromatography using 0-5% meoh-DCM to give 3-hydroxy-3- (2-oxo-1H-benzo [ cd) as a brown solid ]Indol-5-yl) azetidine-1-carboxylic acid ester (399 mg, 870.78. Mu. Mol,22% yield). LC-MS (ES) + ):m/z 341.35[M+H] + .
Step 2 4M dioxane-HCl (10 mL) was added to cooled 3-hydroxy-3- (2-oxo-1H-benzo [ cd) at 0deg.C]In a solution of tert-butyl indol-5-yl) azetidine-1-carboxylate (340 mg, 998.91. Mu. Mol) in dioxane (3 mL) and stirred at room temperature for 2 hours. After the reaction is completed, volatiles are removed to give crude 5- (3-hydroxyazetidin-3-yl)-1H-benzo [ cd ]]Indol-2-one hydrochloride (280 mg, 715.25. Mu. Mol,72% yield) is neutralized with triethylamine (pH 7) and then used in the next step. LC-MS (ES) + ):m/z 241.16[M+H] + .
EXAMPLE 39 Synthesis of 3- [5- (1-benzyl-3-fluoro-azetidin-3-yl) -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 100)
Step 1 to well stirred 5- (3-hydroxyazetidin-3-yl) -1H-benzo [ cd ] under nitrogen atmosphere]To a solution of indol-2-one (120 mg, 499.47. Mu. Mol) in anhydrous DCM (5.0 mL) was added benzaldehyde (79.51 mg, 749.20. Mu. Mol, 76.45. Mu.L) followed by acetic acid (59.99 mg, 998.93. Mu. Mol, 57.13. Mu.L). After heating the reaction mixture at 60 ℃ for 2 hours, it was cooled at room temperature and sodium triacetoxyborohydride (529.29 mg,2.50 mmol) was added at 0 ℃. After the addition, the reaction mixture was stirred at room temperature for a further 12 hours. After completion of the reaction, the reaction mass was diluted with DCM (25 mL) and taken up in NaHCO 3 And (5) neutralizing the solution. The organic phase was washed with water/brine and separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by flash column chromatography to give 5- (1-benzyl-3-hydroxy-azetidin-3-yl) -1H-benzo [ cd ]]Indol-2-one (105 mg, 310.48. Mu. Mol,62% yield). LC-MS (ES) + ):m/z 331.37[M+H] + .
Step 2-5- (1-benzyl-3-hydroxy-azetidin-3-yl) -1H-benzo [ cd ] via syringe at-78deg.C]A solution of indol-2-one (84 mg, 254.25. Mu. Mol) in anhydrous DCM (10.0 mL) was added dropwise N-ethyl-N- (trifluoro- $l {4} -sulfanyl) ethylamine e (204.92 mg,1.27mmol, 167.96. Mu.L) and stirred at the same temperature for 1 hour. After completion, the reaction mixture was diluted with DCM (20 mL) and taken up in NaHCO 3 And (5) neutralizing the solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated and dried under reduced pressure to give 5- (1-benzyl-3-fluoro-azetidin-3-yl) -1H-benzo [ cd ]]Indol-2-one (80 mg, 161.27. Mu. Mol,63% yield) was used in the next reaction without further purification. LC-MS (ES) + ):m/z 333.38[M+H] + .
Step 3 to cooled 5- (1-benzyl-3-fluoro-azetidin-3-yl) -1H-benzo [ cd ]]Sodium hydride (60% dispersion in mineral oil) (96.84 mg,2.53 mmol) was added portionwise to a solution of indol-2-one (84 mg, 252.73. Mu. Mol) in dry THF (5 mL) and the temperature maintained <5 ℃. After the addition, the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was then cooled again to 0 ℃ and 3-bromopiperidine-2, 6-dione (242.63 mg,1.26 mmol) was added thereto in portions. After the addition, the resulting solution was heated at 70 ℃ for 1 hour. In 5- (1-benzyl-3-fluoro-azetidin-3-yl) -1H-benzo [ cd ]]After complete exhaustion of the indol-2-one, the reaction mixture was cooled to 0 ℃ and quenched by addition of ice-cold water (10 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), and the combined organics were separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by PREP TLC to give 3- [5- (1-benzyl-3-fluoro-azetidin-3-yl) -2-oxo-benzo [ cd ] as a yellow solid]Indol-1-yl]Piperidine-2, 6-dione (Compound 100,15.2mg, 32.72. Mu. Mol,12.95% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.14(s,1H),8.16(br,1H),8.0(br,1H),7.65-7.63(m,1H),7.58(t,J＝7.28Hz,1H),7.39(br,5H),7.22(d,J＝7.04Hz,1H),5.48(dd,J＝12.84,5.2Hz,1H),5.1(s,2H),3.8-4.0(br,4H),2.95-2.92(m,1H),2.79-2.78(m,1H),2.68-2.65(m,1H),2.12-2.10(m,1H)；LC-MS(ES + ):m/z 444.30[M+H] + .
3- [5- (3-fluoro-1-methyl-azetidin-3-yl) -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (compound 101)
Compound 101 was prepared essentially following the synthesis of compound 100.
LC-MS(ES + ):m/z 368.27[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.13(s,1H),8.12(d,J＝7.56Hz,1H),7.96-7.95(m,1H),7.68-7.66(m,1H),7.57(t,J＝7.28Hz,1H),7.2(d,J＝7.12Hz,1H),5.45(dd,J＝12.8,5.2Hz,1H),3.94-3.8(m,4H),2.95-2.92(m,1H),2.79-2.78(m,1H),2.68-2.67(m,1H),2.40(s,3H),2.12-2.10(m,1H).
EXAMPLE 40 Synthesis of 3- [5- (1-methylazetidin-3-yl) -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 102)
Step 1, stirring 5-bromo-1H-benzo [ cd ] under argon atmosphere at-78deg.C ]To a solution of indol-2-one (1 g,4.03 mmol) in dry THF (10.0 mL) was added phenyl lithium (1.9M, 2.12 mL) in di-n-butyl ether, and the reaction was stirred at the same temperature for 30 min, then butyl lithium (1.62M, 2.74 mL) was added at-78deg.C. After the addition, the temperature was raised to-40 ℃ and the reaction mixture was stirred at the same temperature for 30 minutes. A solution of tert-butyl 3-oxetane-1-carboxylate (690.09 mg,4.03 mmol) in THF (10.0 mL) was added at-78deg.C, and the reaction mixture was allowed to warm to room temperature and stirred for an additional 16 hours. After the reaction was completed, the reaction mixture was quenched with ammonium chloride solution and diluted with ethyl acetate (100 mL). The combined organic phases were washed with water and separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude reaction was purified by flash column chromatography using 0-5% meoh-DCM to give 3-hydroxy-3- (2-oxo-1H-benzo [ cd) as a brown solid]Indol-5-yl) azetidine-1-carboxylic acid tert-butyl ester (390.0 mg,1.05mmol,26% yield). LC-MS (ES) + ):m/z 341.39[M+H] + .
Step 2-3-hydroxy-3- (2-oxo-1H-benzo [ cd ] at 0deg.C]HPLC grade CHCl of tert-butyl indol-5-yl) azetidine-1-carboxylate (360 mg,1.06 mmol) 3 To a solution (10.0 mL) was added triethylamine, 99% (428.10 mg,4.23mmol, 589.67. Mu.L), and stirred for 10 minutes, followed by methanesulfonyl chloride (484.63 mg,4.23mmol, 327.45. Mu.L). The resulting solution was then heated at 80℃for 16 hours. After the reaction was completed, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with sodium bicarbonate solution/brine. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give crude 3-chloro-3- (2-oxo-1H-benzo [ cd) as a brown solid ]Indol-5-yl) azetidine-1-carboxylic acid ester (42)8mg, 644.11. Mu. Mol,61% yield), which was used in the next step without purification. LC-MS (ES) + ):m/z 359.32[M+H] + .
Step 3 to 3-chloro-3- (2-oxo-1H-benzo [ cd ]]Indole-5-yl) azetidine-1-carboxylic acid tert-butyl ester (428 mg,1.19 mmol) to a suspension of tert-butanol (4 mL) and toluene (4 mL) was added Raney nickel 2800 (H) 2 Slurry in O), active catalyst (1.02 g,11.93 mmol) and the reaction mixture was degassed for 10 min and then heated at 100℃for 12 h. After completion, the reaction mixture was cooled to room temperature, filtered through a pad of celite, washed with 10% meoh/dcm. The combined filtrates were then concentrated under reduced pressure to give 3- (2-oxo-1H-benzo [ cd)]Indol-5-yl) azetidine-1-carboxylic acid tert-butyl ester (370 mg, 489.34. Mu. Mol,41% yield), which was used in the next step without purification. LC-MS (ES) + ):m/z 325.39[M+H] + .
Step 4-3- (2-oxo-1H-benzo [ cd) under stirring at 0deg.C]To a solution of tert-butyl indol-5-yl) azetidine-1-carboxylate (370.0 mg,1.14 mmol) in 1, 4-dioxane (3 mL) was added 4M dioxane-HCl (1.14 mmol,10 mL) and the reaction mixture was stirred at room temperature for 16 hours. After completion, the volatiles were removed under reduced pressure to give a solid which was washed with diethyl ether and pentane to give 5- (1-chloroazetidin-3-yl) -1H-benzo [ cd ] as a yellow solid ]Indol-2-one hydrochloride (290.0 mg, 478.16. Mu. Mol,42% yield) was used in the next step without purification. LC-MS (ES) + ):m/z 225.36[M+H] + .
Step 5 to well stirred 5- (1-Chloroazetidin-3-yl) -1H-benzo [ cd ]]To a solution of indol-2-one HCl (90.0 mg,1.11 mmol) in HPLC grade DCM-MeOH (5:2, v/v,7 mL) was added triethylamine, 99% (112.55 mg,1.11mmol, 155.03. Mu.L), and the reaction mixture was stirred at room temperature for 10 min, followed by formaldehyde (66.81 mg,2.22mmol, 61.86. Mu.L) and acetic acid (133.59 mg,2.22mmol, 127.23. Mu.L). The resulting reaction mixture was then heated at 60 ℃ for 3 hours and allowed to reach room temperature, followed by the addition of sodium triacetoxyborohydride (1.22 g,5.75 mmol). After the addition was completed, the reaction mixture was stirred at the same temperature for another 12 hours. After the reaction was complete, the reaction mixture was diluted with 10% MeOH/DCM (50 mL) and washed with saturated sodium bicarbonate solution,and then washed with water/brine solution. The organic fraction was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by combi-flash column chromatography to give 5- (1-methylazetidin-3-yl) -1H-benzo [ cd ]]Indol-2-one (60.0 mg, 188.85. Mu. Mol,17% yield). LC-MS (ES) + ):m/z 239.02[M+H] + .
Step 6-cooling 5- (1-Methylazetidin-3-yl) -1H-benzo [ cd ] ]To a solution of indol-2-one (160.0 mg, 671.47. Mu. Mol) in dry THF (5 mL) was added in portions, maintaining the temperature<5 ℃. After the addition, the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was then cooled again to 0deg.C and 3-bromopiperidine-2, 6-dione (128.93 mg, 671.47. Mu. Mol) was added in portions. After the addition was completed, the resulting solution was heated at 70 ℃ for 1 hour. After completion, the reaction mixture was cooled to 0 ℃ and quenched by addition of ice-cold water (5 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), the combined organics were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by PREP-TLC to give 3- [5- (1-methylazetidin-3-yl) -2-oxo-benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (compound 102,5.8mg, 15.85. Mu. Mol,2% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.11(s,1H),8.07(d,J＝7.28Hz,1H),7.79(d,J＝7.12Hz,1H),7.62(d,J＝8.48Hz,1H),7.51(t,J＝7.32Hz,1H),7.14(d,J＝7.16Hz,1H),5.44-5.42(m,1H),4.38-4.35(m,1H),3.91(m,2H),3.43(m,2H),2.94-2.91(m,1H),2.77-2.62(m,2H),2.32(s,3H),2.10-2.07(m,1H)；LC-MS(ES + ):m/z 350.1[M+H] + .
EXAMPLE 41 3- [5- [ (1-Benzylazetidin-3-yl) methyl ] -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 103)
Step 1, stirring 5-bromo-1H-benzo [ cd ] at-78deg.C under argon atmosphere]To a solution of indol-2-one (1.0 g,4.03 mmol) in dry THF (5.0 mL) was added phenyl lithium (1.8M, 2.24 mL) in di-n-butyl ether, and the reaction was stirred at the same temperature for 30 min, then butyl lithium was added at-78deg.C (1.62M, 2.74 mL). The reaction was warmed to-40 ℃ and stirred at that temperature for 30 minutes. A solution of tert-butyl 3-formylazetidine-1-carboxylate (746.63 mg,4.03mmol, 287.88. Mu.L) in anhydrous THF (5.0 mL) was then added at-78deg.C and stirring continued for 16 h at room temperature. After completion, the reaction mixture was quenched with ammonium chloride solution and diluted with ethyl acetate (100 mL). The combined organic layers were washed with water/brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 0-5% MeOH-DCM to give 3- [ hydroxy- (2-oxo-1H-benzo [ cd) as a brown solid]Indol-5-yl) methyl]Azetidine-1-carboxylic acid tert-butyl ester (470 mg,1.19mmol,30% yield). 1 H NMR(400MHz,DMSO-d 6 )δ10.7(s,1H),7.96(d,J＝7.2Hz,1H),7.84-7.81(m,2H),7.48(t,J＝7.6Hz,1H),6.96(d,J＝7.04Hz,1H),5.92(d,J＝4.32Hz,1H),5.44-5.42(m,1H),3.91(br m,1H),3.75-3.67(m,3H),3.0-2.95(m,1H),1.36(s,9H).LC-MS(ES + ):m/z 255.2[M–Boc+H] + .
Step 2 3- [ hydroxy- (2-oxo-1H-benzo [ cd ] in flame dried 100mL round bottom flask]Indol-5-yl) methyl]HPLC grade CHCl of tert-butyl azetidine-1-carboxylate (350 mg, 987.59. Mu. Mol) 3 (10.0 mL) the solution was cooled to 0deg.C. To the cooled solution was added triethylamine (44399.74 mg,3.95mmol, 550.60. Mu.L), followed by methanesulfonyl chloride (452.51 mg,3.95mmol, 305.75. Mu.L). The resulting reaction mixture was refluxed at 80 ℃ for 4 hours. After completion, the reaction mixture was diluted with DCM (30 mL) and the organic layer was washed with saturated sodium bicarbonate solution, then with water/brine solution. The combined organic phases were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give 3-chloro-3- (2-oxo-1H-benzo [ cd) ]Indol-5-yl) pyrrolidine-1-carboxylic acid tert-butyl ester (400 mg,1.07mmol,99% yield) was used in the next step without purification. LC-MS (ES) + ):m/z 317.25[M–tBu+H] + .
Step 3 to 3- [ chloro- (2-oxo-1H-benzo [ cd ]]Indol-5-yl) methyl]To a suspension of tert-butyl azetidine-1-carboxylate (400 mg,1.07 mmol) in tert-butanol (5 mL) and toluene (5 mL) was added Raney nickel 2800 (H) 2 Slurry in O), active catalyst (459.57 mg,5.36 mmol), the reaction mixture was degassed for 10 min, thenAnd then heated at 100℃for 12 hours. After completion, the reaction mixture was cooled to room temperature, filtered through a pad of celite, and washed with 10% meoh/DCM. The filtrate was washed with cold water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3- [ chloro- (2-oxo-1H-benzo [ cd)]Indol-5-yl) methyl]Azetidine-1-carboxylic acid tert-butyl ester (450 mg,1.21 mmol), which was used in the next step without purification or characterization.
Step 4-3- [ (2-oxo-1H-benzo [ cd ] at 0deg.C]Indol-5-yl) methyl]A solution of tert-butyl azetidine-1-carboxylate (306 mg, 904.26. Mu. Mol) in dioxane (4 mL) was treated with 4M dioxane-HCl (9.04 mmol,2.0 mL) and stirred at room temperature for 12 hours. After the reaction was completed, volatiles were removed under reduced pressure, and the crude product was washed with pentane/diethyl ether and dried sufficiently to give 5- (azetidin-3-ylmethyl) -1H-benzo [ cd ] ]Indol-2-ones; hydrochloride (250 mg,482.00 μmol,53% yield) which was used in the next step without purification. LC-MS (ES) + ):m/z239.45[M+H] + .
Step 5 to 5- (azetidin-3-ylmethyl) -1H-benzo [ cd ]]To a suspension of indol-2-one (150 mg, 629.50. Mu. Mol) in MeOH (5 mL) -DCE (5 mL) was added triethylamine to a pH of 7. To this solution was added acetic acid (113.41 mg,1.89mmol, 108.01. Mu.L), followed by benzaldehyde (133.61 mg,1.26 mmol), and the resulting solution was heated at 60℃for 3 hours. The mixture was then cooled to room temperature, and then sodium triacetoxyborohydride (667.09 mg,3.15 mmol) was added in portions at 0 ℃. The reaction mixture was stirred at room temperature for a further 12 hours. After completion, volatiles were removed and the residue was redissolved in ethyl acetate (50 mL). The organic layer was washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by combi-flash column chromatography to give 5- [ (1-benzyl azetidin-3-yl) methyl]-1H-benzo [ cd ]]Indol-2-one (100 mg, 249.69. Mu. Mol,40% yield). LC-MS (ES) + ):m/z 329.0[M+H] + .
Step 6 sodium hydride (60% dispersion in mineral oil) (58.34 mg,1.52 mmol) was added portionwise to a cooled solution of 5- [ (1-benzyl azetidin-3-yl) methyl ] -1H-benzo [ cd ] indol-2-one (50 mg, 152.25. Mu. Mol) in THF (5 mL) maintaining the temperature <5 ℃. The resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was then cooled to 0deg.C and 3-bromopiperidine-2, 6-dione (146.17 mg, 761.25. Mu. Mol) was added in portions and the solution was heated at 70deg.C for 1 hour. After complete consumption of the starting material, the reaction mixture was cooled to 0 ℃ and quenched by addition of ice-cold water (5 mL). The aqueous layer was extracted with ethyl acetate (3X 50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by PREP TLC to give 3- [5- [ (1-benzylazetidin-3-yl) methyl ] -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione as a yellow solid (compound 103,15mg,34.13 μmol,22% yield).
LC-MS(ES + ):m/z 440.30[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),7.99(d,J＝7.0Hz,1H),7.78(d,J＝8.28Hz,1H),7.62(d,J＝6.68Hz,1H),7.53(t,J＝7.72Hz,1H),7.28-7.25(m,5H),7.14(d,J＝7.16Hz,1H),5.44(dd,J＝11.28,3.32Hz,1H),3.55(s,2H),3.39-3.37(m,2H),3.29-3.27(m,2H),2.94(br m,3H),2.80-2.62(m,3H),2.09(m,1H).
EXAMPLE 42 Synthesis of tert-butyl 3- [ [1- (2, 6-dioxo-3-piperidyl) -2-oxo-benzo [ cd ] indol-5-yl ] methyl ] azetidine-1-carboxylate (Compound 104)
The compound tert-butyl 3- [ (2-oxo-1H-benzo [ cd ] indol-5-yl) methyl ] azetidine-1-carboxylate was prepared in example 41.
To cooled 3- [ (2-oxo-1H-benzo [ cd)]Indol-5-yl) methyl]To a solution of tert-butyl azetidine-1-carboxylate (95 mg, 280.73. Mu. Mol) in anhydrous THF (5 mL) was added sodium hydride (60% dispersion in mineral oil) (107.57 mg,2.81 mmol) in portions, maintaining the temperature<5 ℃. After the addition, the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was then cooled again to 0deg.C and 3-bromopiperidine-2, 6-dione (269.52 mg,1.40 mmol) was added in portions. After the addition was completed, the resulting solution was heated at 70 ℃ for 1 hour. After complete consumption of the starting material, the reaction mixture was cooled to 0 ℃ and purified by addition ofIce-cold water (10 mL) was added to quench. The aqueous layer was extracted with ethyl acetate (3X 50 mL). The combined organics were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by PREP TLC to give 3- [ [1- (2, 6-dioxo-3-piperidinyl) -2-oxo-benzo [ cd) as a yellow solid ]Indol-5-yl]Methyl group]Azetidine-1-carboxylic acid tert-butyl ester (compound 104,9.6mg, 20.82. Mu. Mol,7% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),8.01(d,J＝7.12Hz,1H),7.81(d,J＝8.56Hz,1H),7.68(d,J＝7.2Hz,1H),7.55(t,J＝7.4Hz,1H),7.15(d,J＝7.24Hz,1H),5.45(dd,J＝12.84,5.44Hz,1H),3.83(m,2H),3.65(m,2H),3.43(d,J＝7.84Hz,2H),2.97-2.9(m,2H),2.77-2.63(m,2H),2.10-2.07(m,1H),1.36(s,9H)；LC-MS(ES - ):m/z 448.36[M-H] - .
EXAMPLE 43 Synthesis of 3- [5- [ (1-methylazetidin-3-yl) methyl ] -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 105)
Step 1 into an oven dried nitrogen purged sealed vial, 3- (5-bromo-2-oxo-benzo [ cd)]Indol-1-yl) piperidine-2, 6-dione (450 mg,1.25 mmol) and 3-methyleneazetidine-1-carboxylic acid tert-butyl ester (636.04 mg,3.76 mmol) were dissolved in HPLC grade DMF (3.0 mL). Triethylamine (633.89 mg,6.26mmol, 873.13. Mu.L) was added to the solution, and the reaction mixture was purged with argon for 10 minutes, followed by addition of [1,1' -bis (diphenylphosphino) ferrocene]Palladium (II) dichloride (102.31 mg, 125.29. Mu. Mol). The resulting reaction mixture was heated at 100℃for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and diluted with ethyl acetate (40 mL). The combined organic layers were washed several times with cold water/brine. The organic layer was separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude product which was purified by column chromatography (100-200 mesh silica, 40% -50% ethyl acetate/DCM) to give 3- [ [1- (2, 6-dioxo-3-piperidinyl) -2-oxo-benzo [ cd ] as a pale brown solid ]Indol-5-yl]Methylene group]Azetidine-1-carboxylic acid tert-butyl ester (420 mg, 750.87. Mu. Mol,60% yield). LC-MS (ES) + ):m/z 348.2[M-Boc+H] + .
Step 2 to fully degassed 3- [ [1- (2, 6-dioxo-3-piperidyl) -2-oxo-benzo [ cd ]]Indol-5-yl]Methylene group]To a solution of tert-butyl azetidine-1-carboxylate (420 mg, 938.59. Mu. Mol) in ethanol (5.0 mL) -EtOAc (5.0 mL) was added 10% Pd/C (569.97 mg,4.69 mmol) and the resulting mixture was hydrogenated at hydrogen balloon pressure at room temperature for 1 hour. After completion, the reaction mixture was filtered through a celite pad, washing with ethyl acetate and THF. The filtrate was concentrated under reduced pressure and the crude product was triturated with n-pentane to give 3- [ [1- (2, 6-dioxo-3-piperidinyl) -2-oxo-benzo [ cd ]]Indol-5-yl]Methyl group]Azetidine-1-carboxylic acid tert-butyl ester (350 mg, 583.98. Mu. Mol,62% yield). LC-MS (ES) + ):m/z 350.2[M–Boc+H] + .
Step 3 to 3- [ [1- (2, 6-dioxo-3-piperidyl) -2-oxo-benzo [ cd ] during stirring]Indol-5-yl]Methyl group]To a solution of tert-butyl azetidine-1-carboxylate (420 mg, 934.38. Mu. Mol) in dioxane (3 mL) was added 4M dioxane-HCl (15 mL), and the reaction mixture was stirred at room temperature for 2 hours. After completion of the reaction, the volatiles were evaporated under reduced pressure to give a solid which was washed with diethyl ether and pentane to give 3- [5- [ (1-chloroazetidin-3-yl) methyl ] as a yellow solid ]-2-oxo-benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione hydrochloride (400.0 mg, 527.58. Mu. Mol,56% yield) was used in the next step without purification. LC-MS (ES) + ):m/z 350.0[M+H] + .
Step 4-3- [5- (azetidin-3-ylmethyl) -2-oxo-benzo [ cd ] to stirring]Indol-1-yl]To a solution of piperidine-2, 6-dione (200 mg, 572.44. Mu. Mol) and formaldehyde (38.99 mg,1.14mmol, 47.84. Mu.L) in dry THF (5 mL) was added dibutyltin dichloride (260.90 mg, 858.66. Mu. Mol, 191.84. Mu.L) in portions, and the mixture was stirred in a sealed vial at 60℃for 20 minutes. Subsequently, the reaction mixture was cooled to room temperature and phenylsilane (61.94 mg, 572.44. Mu. Mol, 70.55. Mu.L) was added. The resulting reaction mixture was heated at 80℃for 12 hours. After the reaction was complete, volatiles were removed under reduced pressure and redissolved in 5% MeOH-DCM (20 mL). The organic fraction was washed with water/brine and separated, dried over sodium sulfate and concentrated. The crude product was purified by PREP-TLC to give 3- [5- [ (1-methylazacyclo) heterocycleButan-3-yl) methyl]-2-oxo-benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (compound 105,13.1mg, 32.59. Mu. Mol,6% yield). LC-MS (ES) + ):m/z 364.31[M+H] + .1H NMR(400MHz,DMSO-d 6 ) δ11.12 (s, 1H), 8.04 (d, j=7 hz, 1H), 7.83 (d, j=8.72 hz, 1H), 7.65 (d, j=7.28 hz, 1H), 7.57 (t, j=7.4 hz, 1H), 7.17 (d, j=7.16 hz, 1H), 5.45-5.43 (m, 1H), 3.86-3.85 (m, 2H), 3.69 (m, 2H), 3.47 (d, j=7.44 hz, 2H), 3.07-3.03 (m, 2H), 2.76-2.73 (m, 1H), 2.68 (br s, 4H), 2.10-2.08 (m, 1H). Example 44 is the synthesis of 3- [5- (4, 6-dimethylpyrimidin-2-yl) -2-oxo-benzo [ cd ] ]Indol-1-yl]Piperidine-2, 6-dione (Compound 106)
Step 1 5-bromo-1H-benzo [ cd ] with stirring at 0deg.C]To a solution of indol-2-one (6.0 g,24.19 mmol) in anhydrous DMF (10 mL) was added sodium hydride (60% dispersion in mineral oil) (1.39 g,36.28 mmol). The reaction mixture was stirred at the same temperature under an inert atmosphere for 30 minutes. 1- (chloromethyl) -4-methoxy-benzene (4.55 g,29.02mmol, and 3.79 mL) was then added to the reaction mixture and stirred at room temperature for an additional 30 minutes. After completion, ethyl acetate (100 mL) was added to the reaction mixture. The organic layer was washed with cold water (3X 30 mL) and then brine solution. The organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by combi-flash column chromatography to give 5-bromo-1- [ (4-methoxyphenyl) methyl as a yellow solid]Benzo [ cd ]]Indol-2-one (6.0 g,15.81mmol,65% yield). LC-MS (ES) + ):m/z 370.2[M+H] + .
Step 2-5-bromo-1- [ (4-methoxyphenyl) methyl group was placed in an oven-dried sealed vial under a nitrogen atmosphere]Benzo [ cd ]]Indol-2-one (3.0 g,8.15 mmol) is dissolved in 1,4 dioxane (60 mL) followed by the addition of bis (pinacolato) diboron (3.10 g,12.22 mmol) and potassium acetate (2.40 g,24.44 mmol). The resulting reaction mixture was purged with argon for 15 minutes. Adding cyclopentyl (diphenyl) phosphine to the reaction mixture; dichloromethane; palladium dichloride; iron (665.34 mg, 814.72. Mu. Mol) and the mixture was heated at 100℃for 16 hours. After the completion of the reaction, the reaction mixture, The reaction mixture was cooled to room temperature, filtered through a celite pad, and washed with ethyl acetate. The filtrate was washed with cold water (2×40 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified by flash column chromatography to give 1- [ (4-methoxyphenyl) methyl ] as a yellow solid]-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ cd ]]Indol-2-one (2.9 g,6.98mmol,86% yield). LC-MS (ES) + ):m/z 416.4[M+H] + .
Step 3-1- [ (4-methoxyphenyl) methyl group]-5- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ cd ]]A mixture of indol-2-one (200 mg, 481.59. Mu. Mol), 2-bromo-4, 6-dimethyl-pyrimidine (75.06 mg, 401.33. Mu. Mol) and potassium carbonate (166.40 mg,1.20 mmol) was suspended in a mixture of dioxane (4 mL) and water (1 mL). The resulting reaction mixture was degassed with argon for 10 min, then Pd (dppf) cl2.Dcm (32.77 mg,40.13 μmol) was added and the mixture was stirred at room temperature for 12 h. After the reaction was completed, the reaction mixture was filtered through a filter cartridge and the filtrate was evaporated to dryness. The crude product was diluted with ethyl acetate (50 mL) and washed with water/brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5- (4, 6-dimethylpyrimidin-2-yl) -1- [ (4-methoxyphenyl) methyl ]Benzo [ cd ]]Indol-2-one (110 mg, 250.35. Mu. Mol,62% yield) was used in the next reaction without further purification. LC-MS (ES) + ):m/z 396.4[M+H] + .
Step 4 5- (4, 6-Dimethylpyridin-2-yl) -1- [ (4-methoxyphenyl) methyl with stirring at 0℃]Benzo [ cd ]]To a solution of indol-2-one (158 mg, 399.54. Mu. Mol) in TFA (5.0 mL) was added trifluoromethanesulfonic acid (1.20 g,7.99mmol, 701.33. Mu.L) and stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was evaporated and quenched with saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate (3×25 mL) and washed with water/brine solution. The organic phase was separated, dried over sodium sulfate and concentrated to give crude 5- (4, 6-dimethylpyrimidin-2-yl) -1H-benzo [ cd) as a brown solid]Indol-2-one (67 mg, 238.50. Mu. Mol,60% yield) was used in the next step without purification. LC-MS (ES) + ):m/z 276.2[M+H] + .
Step 5 to cooled 5- (4, 6-dimethyl)Pyrimidin-2-yl) -1H-benzo [ cd]Sodium hydride (60% dispersion in mineral oil) (93.34 mg,2.44 mmol) was added portionwise to a solution of indol-2-one (67.06 mg, 243.60. Mu. Mol) in dry THF (5 mL) and the temperature maintained<5 ℃. Once the addition was complete, the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was then cooled again to 0 ℃ and 3-bromopiperidine-2, 6-dione (233.87 mg,1.22 mmol) was added thereto in portions. After the addition was completed, the resulting solution was heated at 70 ℃ for 1 hour. After completion, the reaction mixture was cooled to 0 ℃ and quenched by addition of ice-cold water. The aqueous layer was extracted with ethyl acetate (3X 50 mL). The combined organics were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by PREP-TLC to give 3- [5- (4, 6-dimethylpyrimidin-2-yl) -2-oxo-benzo [ cd) as a yellow solid ]Indol-1-yl]Piperidine-2, 6-dione (compound 106,20mg, 51.76. Mu. Mol,21% yield). LC-MS (ES) + ):m/z 387.3[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ11.15(s,1H),8.68(dd,J＝8.8,7.44Hz,2H),8.21(d,J＝7.36Hz,1H),7.59(t,J＝7.32Hz,1H),7.36(s,1H),7.20(d,J＝7.08Hz,1H),5.49(dd,J＝1.334,5.08Hz,1H),2.95-2.91(br m,1H),2.8-2.77(m,2H),258(s,6H),2.13-2.08(m,1H).
EXAMPLE 45 Synthesis of 1- (2, 6-dioxo-3-piperidyl) -2-oxo-N- (1-phenylethyl) benzo [ cd ] indole-5-carboxamide (Compound 107)
Step 1 2-methylbut-2-ene (682.45 mg,9.73mmol,1.03 mL) was added to stirred 1- (2, 6-dioxo-3-piperidinyl) -2-oxo-benzo [ cd) at 0-5 ℃]In a solution of indole-5-carbaldehyde (200 mg, 648.74. Mu. Mol) in tert-butanol (12 mL). To the mixture was added dropwise an aqueous solution of sodium chlorite (293.36 mg,3.24 mmol) and sodium dihydrogen phosphate hydrate (447.61 mg,3.24 mmol), and stirring was continued at room temperature for 16 hours. After completion, the reaction mixture was evaporated to dryness under reduced pressure and 10mL of 10 (M) NaOH was added. The resulting solution was extracted with ethyl acetate, the organic layer was discarded, and the aqueous layer was acidified with 1N HCl solution. Filtering off the observed yellow precipitate and drying in vacuo to giveTo 1- (2, 6-dioxo-3-piperidyl) -2-oxo-benzo [ cd ]]Indole-5-carboxylic acid (120 mg, 336.74. Mu. Mol,52% yield); LC-MS (ES) + ):m/z 325[M+H] + .
Step 2 to stirring 1- (2, 6-dioxo-3-piperidyl) -2-oxo-benzo [ cd ]]To a solution of indole-5-carboxylic acid (30 mg, 92.51. Mu. Mol) in DMF (1 mL) was added DIPEA (23.91 mg, 185.02. Mu. Mol, 32.23. Mu.L) and HATU (35.18 mg, 92.51. Mu. Mol) and the mixture was stirred at room temperature for 15 min. 1-Phenylethylamine (12.33 mg, 101.76. Mu. Mol, 13.05. Mu.L) was added to the solution, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was purified by reverse phase preparative HPLC to give 1- (2, 6-dioxo-3-piperidyl) -2-oxo-N- (1-phenylethyl) benzo [ cd ] ]Indole-5-carboxamide (Compound 107,8.92mg, 20.87. Mu. Mol,23% yield). LC-MS (ES) + ):m/z 428[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ11.09(br.s,1H),9.20(d,J＝8Hz,1H),8.16(d,J＝8Hz,1H),8.00(dd,J＝8Hz,0.8Hz,1H),7.81(dd,J＝8Hz,4Hz,1H),7.55(t,J＝8Hz,1H),7.46(d,J＝8Hz,2H),7.37(t,J＝8Hz,2H),7.26(t,J＝8Hz,1H),7.20(d,J＝8Hz,1H),5.46(q,J＝8Hz,1H),2.96-2.90(m,1H),2.78(t,J＝8Hz,1H),2.67-2.64(m,1H),2.13-2.08(m,1H),1.51(d,J＝8Hz,3H).
Compound 108-compound 112 was prepared essentially following the synthesis of compound 107.
N- (1-cyclohexylethyl) -1- (2, 6-dioxopiperidin-3-yl) -2-oxo-1, 2-dihydrobenzo [ cd ] indole-5-carboxamide (Compound 108)
LC-MS(ES + ):m/z 434[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.13(s,1H),8.50(d,J＝8Hz,1H),8.14(d,J＝8Hz,1H),7.91(d,J＝8Hz,1H),7.83(d,J＝8Hz,1H),7.57(t,J＝8Hz,1H),7.19(d,J＝8Hz,1H),5.46(q,J＝4Hz,1H),3.94(q,J＝8Hz,1H),2.92(t,J＝8Hz,1H),2.79-2.75(m,1H),2.66(d,J＝16Hz,1H),2.11-2.13(m,1H),1.84-1.72(m,4H),1.64(s,1H),1.44(d,J＝8Hz,1H),1.23-1.19(m,8H).
1- (2, 6-Dioxopiperidin-3-yl) -N- (1- (2-methoxyphenyl) ethyl) -2-oxo-1, 2-dihydrobenzo [ cd ] indole-5-carboxamide (Compound 109)
LC-MS(ES + ):m/z 458[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.18(br.s,1H),9.14(d,J＝8Hz,1H),8.17(d,J＝8Hz,1H),8.01(d,J＝8Hz,1H),7.80(d,J＝8Hz,1H),7.55(m,1H),7.40(d,J＝8Hz,1H),7.25(d,J＝8Hz,1H),7.18(d,J＝8Hz,1H),7.02(d,J＝8Hz,1H),6.96(d,J＝8Hz,1H),5.52(t,J＝8Hz,1H),5.46(t,J＝8Hz,1H),3.87(s,3H),2.95-2.91(m,1H),2.79-2.75(m,1H),2.66(d,J＝12Hz,1H)；2.13-2.10(m,1H),1.74(s,2H),1.42(d,J＝8Hz,3H).
1- (2, 6-Dioxopiperidin-3-yl) -2-oxo-N- (2, 2-trifluoro-1-phenylethyl) -1, 2-dihydrobenzo [ cd ] indole-5-carboxamide (Compound 110)
LC-MS(ES + ):m/z 482[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.15(br.s,1H),10.06(d,J＝8Hz,1H),8.19(d,J＝8Hz,1H),7.99(d,J＝8Hz,1H),7.71(d,J＝8Hz,3H),7.59(t,J＝8Hz,1H),7.46(d,J＝8Hz,3H),7.22(d,J＝8Hz,1H),6.15(t,J＝8Hz,1H),5.46(d,J＝8Hz,1H),2.95-2.92(m,1H),2.82-2.73(m,1H),2.66(d,J＝8Hz,1H),2.12-2.08(m,1H).
1- (2, 6-Dioxopiperidin-3-yl) -N- (2-methyl-1-phenylpropyl) -2-oxo-1, 2-dihydrobenzo [ cd ] indole-5-carboxamide (Compound 111)
LC-MS(ES + ):m/z 456[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.12(s,1H),9.14(d,J＝8Hz,1H),8.16(d,J＝8Hz,1H),7.91(q,J＝4Hz,1H),7.70(t,J＝8Hz,1H),7.53(t,J＝8Hz,1H),7.43(d,J＝8Hz,1H),7.36(t,J＝8Hz,1H),7.27(d,J＝8Hz,1H),7.18(d,J＝8Hz,1H),5.46(q,J＝8Hz,1H),4.82(t,J＝8Hz,1H),2.99-2.90(m,1H),2.81-2.71(m,1H),2.66(d,J＝16Hz,1H),2.13-2.08(m,2H),1.05(d,J＝8Hz,3H),0.78(d,J＝8Hz,3H).
1- (2, 6-Dioxopiperidin-3-yl) -N-isopropyl-2-oxo-1, 2-dihydrobenzo [ cd ] indole-5-carboxamide (Compound 112)
LC-MS(ES + ):m/z 366[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.11(br.s,1H),8.59(d,J＝8Hz,1H),8.13(d,J＝8Hz,1H),7.92(d,J＝8Hz,1H),7.86(d,J＝8Hz,1H),7.57(t,J＝8Hz,1H),7.19(d,J＝8Hz,1H),5.49-5.44(m,1H),4.21-4.15(m,1H),2.98-2.95(m,1H),2.82-2.63(m,2H),2.13-2.10(m,1H),1.23-1.15(m,6H).
EXAMPLE 46 Synthesis of 1- (2, 6-dioxopiperidin-3-yl) -2-oxo-1, 2-dihydrobenzo [ cd ] indole-5-carboxylic acid (Compound 113)
Step 1 to ice-cold 5-bromo-1H-benzo [ cd ]]To a solution of indol-2-one (5 g,20.16 mmol) in THF (70 mL) was added NaH (60% dispersion in mineral oil) (23.17 g,604.66 mmol) and the reaction stirred at room temperature for 15 min. The reaction was then cooled to 0 ℃ and 3-bromo-glutarimide (27.09 g,141.09 mmol) was slowly added to the mixture and heated to reflux for 1 hour. After completion, the reaction mixture was diluted with ethyl acetate and poured into ice-cold water. The separated organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by combi-flash column chromatography (45% etoac/DCM) to give 3- (5-bromo-2-oxo-benzo [ cd) as a pale yellow solid ]Indol-1-yl) piperidin-26-dione (6 g,15.87mmol,79% yield). LC-MS (ES) + ):m/z 359[M+H] + .
Step 2 to 3- (5-bromo-2-oxo-benzo [ cd)]To a solution of indol-1-yl) piperidine-2, 6-dione (300 mg, 835.25. Mu. Mol) in DMF-H2O mixture (25:1, 5.2 mL) was added triethylamine (127.34 mg,1.26mmol, 175.40. Mu.L) and the resulting solution was degassed and backfilled with argon for 5 min. Xanthene (83.30 mg, 143.97. Mu. Mol) and Pd (OAc) were then added 2 (28.25 mg, 125.84. Mu. Mol) the mixture was degassed and backfilled with argon for 2 minutes. The reaction mixture was purged with a carbon monoxide filled balloon and heated at 80 ℃ under this atmosphere for 16 hours. After the completion of the reaction, the reaction mixture was purified by reverse phase preparative purification to give 1- (2, 6-dioxo-3-piperidyl) -2-oxo-benzo [ cd ]]Indole-5-carboxylic acid (compound 113,20.29mg, 62.57. Mu. Mol,7% yield). LC-MS (ES) + ):m/z 325[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ11.15(s,1H),8.40(d,J＝8Hz,2H),8.14(d,J＝8Hz,1H),7.60(q,J＝4Hz,1H),7.20(d,J＝8Hz,1H),5.47(t,J＝8Hz,1H),2.93(d,J＝12Hz,1H),2.76(d,J＝12Hz,1H),2.65(d,J＝16Hz,1H),2.11(d,J＝8Hz,1H).
EXAMPLE 47 Synthesis of 3- (5-fluoro-2-oxo-benzo [ cd ] indol-1-yl) piperidine-2, 6-dione
Step 1 to stirring 5-bromo-1H-benzo [ cd ]]To a solution of indol-2-one (25 g,100.78 mmol) and diphenylazone (36.53 g,201.55mmol,33.82 mL) in toluene (1500 mL) was added sodium tert-butoxide (29.05 g,302.33 mmol) and the resulting reaction mixture was degassed with argon for 10 min. (5-diphenylphosphino-9, 9-dimethyl-xanthen-4-yl) -diphenyl-phosphine (11.66 g,20.16 mmol) and (1 e,4 e) -1, 5-diphenylpenta-1, 4-dien-3-one are then added; palladium (9.23 g,10.08 mmol) and the reaction mixture was heated at 80℃for 16 hours. After completion, the reaction mixture was diluted with cold water and extracted twice with ethyl acetate. The organic layer was then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was purified by flash column chromatography (100-200 mesh silica, 0-20% EtOAc/hexanes) Conversion to give 5- (benzhydryleneamino) -1H-benzo [ cd ] as a yellow solid]Indol-2-one (20 g,42% yield). LC-MS (ES) + ):m/z 349.4[M+H] + .
Step 2 to stirring 5- (benzhydryleneamino) -1H-benzo [ cd ] at 0 ℃]To a solution of indol-2-one (10 g,28.70 mmol) in THF (100 mL) was added sodium hydride (60% dispersion in mineral oil) (16.50 g,430.54 mmol) in portions. The reaction mixture was then slowly warmed to room temperature and stirred for 1 hour, then cooled to 0 ℃ and 3-bromo-glutarimide (33.07 g,172.22 mmol) was added in portions. The reaction mixture was warmed to room temperature and heated at 70 ℃ for 4 hours. After the reaction was completed, the reaction mixture was slowly poured into crushed ice. The aqueous layer was extracted with ethyl acetate (3×), and the combined organic layers were separated, dried over sodium sulfate and concentrated under reduced pressure. The crude product was triturated with diethyl ether and pentane to give the desired compound 3- [5- (benzhydryleneamino) -2-oxo-benzo [ cd ] as a yellow solid]Indol-1-yl]Piperidine-2, 6-dione (10 g,76% yield). LC-MS (ES) + ):m/z460.0[M+H] + .
Step 3 to stirred 3- [5- (benzhydrylideneamino) -2-oxo-benzo [ cd ]]Indol-1-yl]To a solution of piperidine-2, 6-dione (10 g,21.76 mmol) in THF (100 mL) was added 15mL of aqueous HCl (2N), and the resulting reaction mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was evaporated to dryness, dioxane-HCl (20 mL) was added and stirred for 30 min. The mixture was concentrated in vacuo and the residue was triturated with ether, basified with saturated sodium bicarbonate solution, and washed with 30% etoac/hexanes. The solid was filtered and dried in vacuo to give 3- (5-amino-2-oxo-benzo [ cd) as a yellow solid ]Indol-1-yl) piperidine-2, 6-dione (5.5 g,86% yield). LC-MS (ES) + ):m/z 296.2[M+H] + .
Step 4-3- (5-amino-2-oxo-benzo [ cd) with stirring at 0deg.C]To a solution of indol-1-yl) piperidine-2, 6-dione (4 g,13.55 mmol) in THF (8 mL) was added 48% trifluoroborane hydrofluoric acid salt (1.19 g,13.55mmol,40 mL), followed by a solution of sodium nitrite (2.80 g,40.64mmol,1.29 mL) in water (4 mL). The reaction mixture was stirred at this temperature for 1 hour, then sodium tetrafluoroborate (7.44 g,67.73 mmol) was added. The resulting reaction mixture was then warmed to room temperatureTemperature. The solid precipitate was filtered, washed with diethyl ether and dried under high vacuum to give the corresponding diazonium salt as a brown solid. The resulting solid was then suspended in para-xylene (50 mL) and the mixture was heated at 140 ℃ for 2 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica, 0-15% etoac/hexanes) to give 3- (5-fluoro-2-oxo-benzo [ cd) as a yellow solid]Indol-1-yl) piperidine-2, 6-dione (2.2 g,53% yield). LC-MS (ES) + ):m/z 299.0[M+H] + .
EXAMPLE 48 Synthesis of 3- [5- (4-methylpiperazin-1-yl) -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 114)
To a stirred solution of 1-methylpiperazine (20.15 mg, 201.16. Mu. Mol, 22.31. Mu.L) in HPLC grade DMAC (0.5 mL) was added DIPEA (21.67 mg, 167.63. Mu. Mol, 29.20. Mu.L) and stirred for 30 minutes, followed by 3- (5-fluoro-2-oxo-benzo [ cd)]Indol-1-yl) piperidine-2, 6-dione (50 mg, 167.63. Mu. Mol). The resulting solution was heated at 90 ℃ for a further 12 hours. After completion of the reaction, ice-cold water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (3×25 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give a crude residue which was purified by PREP-TLC to give 3- [5- (4-methylpiperazin-1-yl) -2-oxo-benzo [ cd ] as a white solid]Indol-1-yl]Piperidine-2, 6-dione (Compound 114,37mg, 97.77. Mu. Mol,58% yield). LC-MS (ES) + ):m/z 379.34[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ11.09(s,1H),7.95(d,J＝7.72Hz,1H),7.60(d,J＝8.64Hz,1H),7.43(t,J＝7.36Hz,1H),7.16(d,J＝7.72Hz,1H),7.07(d,J＝7.12Hz,1H),5.40(dd,J＝12.48,5.12Hz,1H),2.96-2.93(m,1H),2.78-2.71(m,1H),2.62(br s,5H),2.49(br s,4H),2.18(s,3H),1.98(m,1H).
Compound 115 and compound 116 were prepared essentially according to the synthesis of compound 114 in example 48 using the appropriate amine starting materials.
3- [5- (4-Benzylpiperazin-1-yl) -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 115)
LC-MS(ES + ):m/z 455.36[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.08(s,1H),7.95(d,J＝7.68Hz,1H),7.60(d,J＝8.6Hz,1H),7.42(t,J＝7.64Hz,1H),7.36 -7.33(m,3H),7.29-7.28(m,2H),7.16(d,J＝7.76Hz,1H),7.07(d,J＝7.16Hz,1H),5.40(dd,J＝12.44,4.64Hz,1H),3.60(s,2H),3.38-3.31(br,4H),2.98-2.94(m,1H),2.78-2.71(m,1H),2.67(br,5H),2.06-2.03(m,1H).
3- [5- [ (1-Benzylpyrrolidin-3-yl) -methyl-amino ] -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (compound 116)
LC-MS(ES + ):m/z 469.3[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.08(s,1H),7.95(d,J＝7.68Hz,1H),7.60(d,J＝8.6Hz,1H),7.42(t,J＝7.64Hz,1H),7.36 -7.33(m,3H),7.29-7.28(m,2H),7.16(d,J＝7.76Hz,1H),7.07(d,J＝7.16Hz,1H),5.40(dd,J＝12.44,4.64Hz,1H),3.60(s,2H),3.38-3.31(br,4H),2.98-2.94(m,1H),2.78-2.71(m,1H),2.67(br,5H),2.06-2.03(m,1H).
EXAMPLE 49 Synthesis of 3- [5- [ (1R) -2- [3- (3-fluorophenoxy) azetidin-1-yl ] cyclohexyloxy ] -2-oxo-benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (Compound 117)
Step 1 3-hydroxyazetidine-1-carboxylic acid tert-butyl ester (3 g,17.32 mmol) was dissolved in anhydrous DCM (4 mL) and cooled in a flame-dried 100mL round bottom flask under an argon atmosphereTo 0 ℃. To the cooled solution was added triethylamine (2.63 g,25.98mmol,3.62 ml) dropwise, and the mixture was stirred at the same temperature for 30 minutes. Methanesulfonyl chloride (2.38 g,20.78mmol,1.61 ml) was then added via syringe and the resulting reaction mixture was stirred at room temperature for an additional 16 hours. After completion, the reaction mixture was diluted with DCM (25 mL) and washed with saturated sodium bicarbonate solution and brine solution. The organic phase was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 3-methylsulfonyloxy-butane-1-carboxylic acid tert-butyl ester (3.5 g,11.84mmol,68% yield), which was used in the next step without any purification. 1 H NMR(400MHz,DMSO-d 6 )δ5.27-5.22(m,1H),4.23-4.19(m,2H),3.93-3.90(m,2H),3.24(s,3H),1.36(s,9H).
Step 2 cesium carbonate (3.20 g,9.83 mmol) was added to a well stirred solution of 3-fluorophenol (807.88 mg,7.21mmol, 651.52. Mu.L) in HPLC grade DMF (10 mL) at room temperature. After stirring at this temperature for 20 minutes, 3-methylsulfonyloxy-butane-1-carboxylic acid tert-butyl ester (2 g,6.55 mmol) was added and the reaction was stirred overnight. After completion, the reaction mixture was diluted with ethyl acetate (30 mL) and poured into ice water (25 mL). The organic phase was washed with brine solution and separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography to give tert-butyl 3- (3-fluorophenoxy) azetidine-1-carboxylate (1.6 g,4.01mmol,61% yield). LC-MS (ES) + ):m/z 212.2[M-tBu+H] + .
Step 3 to tert-butyl 3- (3-fluorophenoxy) azetidine-1-carboxylate (1.5 g,5.61 mmol) was added 4M dioxane-HCl (14.03 mL) at 0deg.C. After stirring at this temperature for 30 minutes, the reaction mixture was allowed to slowly warm to room temperature and stirred for an additional 12 hours. After completion, the volatiles were removed under reduced pressure to give a semi-solid which was triturated with pentane and dried in vacuo to give 3- (3-fluorophenoxy) azetidine hydrochloride as an off-white solid (1 g,2.46mmol,44% yield) which was used in the next reaction without further purification. LC-MS (ES) + ):m/z 168.22[M+H] + .
Step 4-7-oxabicyclo [4.1.0 ] at room temperature with sufficient agitation]To a solution of heptane (616.40 mg,6.28 mmol) in HPLC grade acetonitrile (10 mL) was addedLithium perchlorate (222.73 mg,2.09 mmol). After stirring for 10 minutes, 3- (3-fluorophenoxy) azetidine (700 mg,4.19mmol,2.89 mL) was added and the resulting mixture was heated at 80℃overnight. After completion, the solvent was removed under reduced pressure to give a crude residue, which was then diluted with ethyl acetate (25 mL) and washed with water and brine. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was triturated with pentane and dried in vacuo to give 2- [ [3- (3-fluorophenoxy) cyclobutyl as a yellow solid ]Amino group]Cyclohexanol (900 mg,2.90mmol,69% yield), which was used in the next step without further purification. LC-MS (ES) + ):m/z 266.19[M+H] + .
Step 5 to cooled (1R) -2- [3- (3-fluorophenoxy) azetidin-1-yl]To a solution of cyclohexanol (80 mg, 301.52. Mu. Mol) in anhydrous THF (5 mL) was added sodium hydride (60% dispersion in mineral oil) (115.53 mg,3.02 mmol) in portions, maintaining temperature<5 ℃. The resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was cooled to 0deg.C and 3- (5-fluoro-2-oxo-benzo [ cd) was added in portions]Indol-1-yl) piperidine-2, 6-dione (89.93 mg, 301.52. Mu. Mol) was then heated at 70℃for 1 hour. After complete consumption of the starting material, the reaction mixture was cooled to 0 ℃ and quenched with ice-cold water (10 mL). The aqueous layer was extracted with ethyl acetate (3X 50 mL). The combined organics were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by PREP-TLC to give 3- [5- [ (1R) -2- [3- (3-fluorophenoxy) azetidin-1-yl as a yellow solid]Cyclohexyloxy radical]-2-oxo-benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (compound 117,27mg, 49.24. Mu. Mol,16% yield). LC-MS (ES) + ):m/z 544.36[M+H] + . 1 H NMR(400MHz,DMSO-d 6 ) δ11.10 (s, 1H), 8.02 (d, J=7.88 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.45 (t, J=7.28 Hz, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.28-7.24 (m, 1H), 7.12 (d, J=6.92 Hz, 1H), 6.73 (t, J=8.08 Hz, 1H), 6.66-6.62 (m, 2H), 5.42-5.40 (m, 1H), 4.72-4.71 (m, 1H), 4.59 (br, 1H), 3.79 (br m, 1H), 3.70 (m, 1H), 3.28-3.07 (m, 1H), 2.94-2.91 (m, 1H), 2.75-2.61 (m, 3H), 2.08 (m, 2H), 5.42-5.40 (m, 1H), 4.72 (br, 1H), 3.79 (br, 1H), 3.9 (br, 1H), 3.94-2.91 (m, 1H), 3.70 (br, 1H), 3.9 (2H), 2.9 (2S-2H), 1.9 (2S-1H) and 1.80 (1S-1H) ]Amino group]Benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (chemical)Composite 118
Step 1N- [ (1S, 2S) -2-aminocyclohexyl group under stirring at 0 ℃]To a solution of tert-butyl carbamate (0.25 g,1.17 mmol) and acetone (203.26 mg,3.50mmol, 256.97. Mu.L) in methanol (2.5 mL) was added sodium borohydride (44.13 mg,1.17mmol, 41.25. Mu.L). The reaction mixture was then warmed to ambient temperature and stirred for 16 hours. After the reaction was completed, the reaction mixture was quenched with saturated ammonium chloride solution and the volatiles were evaporated under reduced pressure. The aqueous layer was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N- [ (1S, 2S) -2- (isopropylamino) cyclohexyl as a colorless liquid]Tert-butyl carbamate (0.2 g, 741.08. Mu. Mol,64% yield) was a colorless liquid. LC-MS (ES) + ):m/z 257.5[M+H] + .
Step 2 Ether-HCl (2M, 4 mL) was added to N- [ (1S, 2S) -2- (isopropylamino) cyclohexyl at 0deg.C under argon atmosphere]Tert-butyl carbamate (200 mg, 780.08. Mu. Mol). The reaction mixture was then warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, co-distilled with DCM and N-pentane, and then dried under reduced pressure to give (1 s,2 s) -N2-isopropylcyclohexane-1, 2-diamine hydrochloride as a colorless gum (140 mg,653.77 μmol,84% yield). LC-MS (ES) + ):m/z 157.0[M+H] + .
Step 3 to a stirred solution of (1S, 2S) -N2-isopropylcyclohexane-1, 2-diamine (140 mg, 895.90. Mu. Mol) in DMAc (5 mL) was added DIPEA (347.37 mg,2.69mmol, 468.15. Mu.L), followed by 3- (5-fluoro-2-oxo-benzo [ cd)]Indol-1-yl) piperidine-2, 6-dione (267.22 mg, 895.90. Mu. Mol) and the resulting mixture was heated at 90℃for 12 hours. After completion, the reaction mixture was purified by reverse phase prep HPLC to give 3- [ 2-oxo-5- [ [ (1 s,2 s) -2- (isopropylamino) cyclohexyl]Amino group]Benzo [ cd ]]Indol-1-yl]Piperidine-2, 6-dione (Compound 118,4.38mg, 9.77. Mu. Mol,1% yield). LC-MS (ES) + ):m/z 435.35[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ11.05(s,1H),8.32(br.s,1H),7.88(d,J＝8.0Hz,1H),7.82(d,J＝8.6Hz,1H),7.40(t,J＝7.4Hz,1H),7.10-7.04(m,2H),6.88(d,J＝8.0Hz,1H),5.39-5.35(m,1H),3.78(br.s,1H),3.55(br.s,1H),3.33(br.s,1H),2.97-2.90(m,1H),2.79-2.61(m,3H),2.24(d,J＝10.2Hz,1H),2.12(d,J＝11.4Hz,1H),2.07-2.00(m,1H),1.83(d,J＝11.0Hz,1H),1.73(d,J＝10.5Hz,1H),1.47-1.30(m,4H),1.28-1.24(m,2H),1.26(t,J＝8.0Hz,3H).
3- [ 2-oxo-5- [ [ (1R, 2R) -2- (isopropylamino) cyclohexyl ] amino ] benzo [ cd ] indol-1-yl ] piperidine-2, 6-dione (compound 119)
Compound 119 was prepared essentially following the synthesis of compound 118.
LC-MS(ES + ):m/z 435.35[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.05(s,1H),8.32(br.s,1H),7.88(d,J＝8.0Hz,1H),7.82(d,J＝8.6Hz,1H),7.40(t,J＝7.4Hz,1H),7.10-7.04(m,2H),6.88(d,J＝8.0Hz,1H),5.39-5.35(m,1H),3.78(br.s,1H),3.55(br.s,1H),3.33(br.s,1H),2.97-2.90(m,1H),2.79-2.61(m,3H),2.24(d,J＝10.2Hz,1H),2.12(d,J＝11.4Hz,1H),2.07-2.00(m,1H),1.83(d,J＝11.0Hz,1H),1.73(d,J＝10.5Hz,1H),1.47-1.30(m,4H),1.28-1.24(m,2H),1.26(t,J＝8.0Hz,3H).
EXAMPLE 51 Synthesis of 3- [18- (4-Benzylpiperazin-1-yl) -24-oxo-26, 30-diazatricyclododecane-5, 7 (19), 8 (26), 17 (20), 18 (21) -penten-30-yl ] piperidine-2, 6-dione (Compound 120)
Step 1 to a well stirred solution of ethyl 3-amino-4-bromo-benzoate (20 g,81.94 mmol) in ethanol (100 mL) was added 5- (methoxymethylene) -2, 2-dimethyl-1, 3-dioxane-4, 6-dione (12.00 g,64.46 mmol) and the reaction mixture was heated at 80℃overnight. After completion, the solvent was removed under reduced pressure to give a crude residue, which was then washed with pentane, followed by 50% Et 2 O/pentane washing to give 4-bromo-3- [ (2, 2-dimethyl-4, 6-dioxo-1, 3-dioxan-5-yiidene) methylamino as a yellow solid]Ethyl benzoate (25 g,50.23mmol,61% yield). 1 HNMR(400MHz,DMSO-d 6 )δ11.51(d,J＝13.8Hz,1H),8.74(t,J＝7.2Hz,1H),8.22(d,J＝1.16Hz,1H),7.91(d,J＝8.32Hz,1H),7.74-7.71(m,1H),4.39-4.33(q,2H),1.7(s,6H),1.34(t,J＝7.08Hz,1H).
Step 2-4-bromo-3- [ (2, 2-dimethyl-4, 6-dioxo-1, 3-dioxan-5-yiidene) methylamino]Ph ethyl benzoate (20 g,50.23 mmol) 2 A solution of O (40 mL) was heated at 260℃for 20 min. The reaction mass was cooled to room temperature and poured into hexane. The resulting semi-solid was filtered, washed with hexane and then 50% pentane/Et 2 O was washed several times to give ethyl 8-bromo-4-oxo-1H-quinoline-5-carboxylate (12 g,31.61mmol,63% yield), which was used in the next step without further purification. LC-MS (ES) + ):m/z 296.24[M+H] + .
Step 3A solution of ethyl 8-bromo-4-oxo-1H-quinoline-5-carboxylate (12 g,40.52 mmol) and phosphorus oxybromide (69.71 g,243.15mmol,24.72 mL) in HPLC grade DCM (25 mL) was heated at 140℃for 3H. After completion, the reaction mixture was diluted with DCM (200 mL) and saturated NaHCO 3 The solution was washed, then with brine solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography (hexane to 100% dcm as eluent) to give ethyl 4, 8-dibromoquinoline-5-carboxylate (8.5 g,23.68mmol,70% yield) as a colorless solid. LC-MS (ES) + ):m/z 360.15[M+H] + .
Step 4 to a solution of ethyl 4, 8-dibromoquinoline-5-carboxylate (5.5 g,15.32 mmol) in HPLC grade NMP (30 mL) was added 4-methoxybenzylamine (4.20 g,30.64mmol,4.00 mL) and the reaction mixture was heated at 80℃for 5h. After completion, the reaction was diluted with ethyl acetate (200 mL) and then washed with water and brine. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue, which was then purified by silica gel column chromatography to give 14-bromo-19- [ (4-methoxyphenyl) methyl as a white solid]-18, 19-diazatricyclododecane-5 (12), 6 (14), 7 (13), 8%18 15-penten-17-one (4.5 g,9.99mmol,65% yield). LC-MS (ES) + ):m/z 371.1[M+H] + .
Step 5 to solid Compound 14-bromo-19- [ (4-methoxyphenyl) methyl at 0deg.C]-18, 19-diazatricyclododecane-5 (12), 6 (14), 7 (13), 8 (18), 15-pentaen-17-one (4 g,10.83 mmol) TFA (10.0 mL) was added followed by trifluoromethanesulfonic acid (16.26 g,108.34mmol,9.51 mL) and stirred at room temperature for 30 minutes. The reaction mixture was heated at 70 ℃ for a further 5 hours. After completion, the reaction was diluted with DCM (150 mL) and slowly poured into ice-cold water. The resulting solution was then taken up in Na 2 CO 3 And (5) neutralizing the solution. The organic phase was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude residue, which was then purified by silica gel column chromatography to give 6-bromo-10, 11-diazatricyclododecane- (4), 1 (6), 2 (5), 3 (10), 7-pentaen-9-one (2 g,4.58mmol,42% yield) as a white solid. LC-MS (ES) + ):m/z 248.8[M+H] + .
Step 6 1-Benzylpiperazine (142.10 mg, 806.21. Mu. Mol) was added to a well-stirred solution of 6-bromo-10, 11-diazatricyclododecane- (4), 1 (6), 2 (5), 3 (10), 7-penten-9-one (100.40 mg, 403.10. Mu. Mol) in HPLC grade NMP (250.00. Mu.L), and the reaction mass was heated in a sealed vial at 100℃overnight. After completion, the solution was cooled to room temperature and poured into ice-cold water (5 mL). The aqueous portion was extracted with ethyl acetate (3×25 mL), separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a crude residue, which was then purified by flash chromatography to give pure compound 17- (4-benzylpiperazin-1-yl) -21, 22-diazatricyclododecane-5 (15), 6 (17), 7 (16), 8 (21), 18-pentaen-20-one (100 mg,284.55 μmol,71% yield) as a white solid. LC-MS (ES) + ):m/z 345.36[M+H] + .
Step 7 sodium hydride (60% dispersion in mineral oil) (296.13 mg,7.40 mmol) was added in portions to a cooled solution of 17- (4-benzylpiperazin-1-yl) -21, 22-diazatricyclododecane-5, 7 (16), 8 (21), 15 (18), 17 (19) -penta-en-20-one (85 mg, 246.80. Mu. Mol) in dry THF (15 mL) maintaining the temperature<5 ℃. After the addition, the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was then cooled again to 0℃and partitioned into 3-bromopiperidine-2, 6-dione (568.66 mg,2.96 mmol) was added in portions and the resulting solution was heated at 70℃for 1 hour. After complete exhaustion of 17- (4-benzylpiperazin-1-yl) -21, 22-diazatricyclododecane-5, 7 (16), 8 (21), 15 (18), 17 (19) -pentaen-20-one, the reaction mixture was cooled to 0 ℃ and quenched by addition of ice-cold water (5 mL). The aqueous layer was extracted with ethyl acetate (3X 50 mL). The combined organics were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound which was purified by PRE PTLC to give 3- [18- (4-benzylpiperazin-1-yl) -24-oxo-26, 30-diazatricyclododecane-5, 7 (19), 8 (26), 17 (20), 18 (21) -penten-30-yl as a yellow solid]Piperidine-2, 6-dione (Compound 120,19mg, 38.44. Mu. Mol,16% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.11(s,1H),8.65(d,J＝4.68Hz,1H),7.89(d,J＝8.0Hz,1H),7.36-7.35(m,4H),7.27(br m,1H),7.12-7.07(m,2H),5.40(dd,J＝12.4,5.28Hz,1H),4.08-4.01(m,4H),3.56(s,2H),2.95-2.92(m,1H),2.75-2.61(m,6H),2.08-1.98(m,1H).LC-MS(ES + ):m/z 456.31[M+H] + .
3- [12- (4-methylpiperazin-1-yl) -18-oxo-20, 24-diazatricyclododecane-1, 3 (13), 4 (20), 11 (14), 12 (15) -penten-24-yl ] piperidine-2, 6-dione (compound 121)
Compound 121 was prepared essentially following the synthesis of compound 120.
LC-MS(ES + ):m/z 380.39[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ11.11(s,1H),8.67(d,J＝4.68Hz,1H),7.90(d,J＝8.28Hz,1H),7.13-7.09(m,2H),5.40(dd,J＝11.84,3.48Hz,1H),3.95(br s,4H),3.31(br,4H),2.92-2.89(m,1H),2.72-2.56(m,2H),2.32(s,3H),2.08-2.06(m,1H).
EXAMPLE 52 27- (2, 6-dioxo-3-piperidyl) -20-oxo-N- (1-phenylethyl) -24, 27-diazatricyclododecane-6, 8 (15), 9 (24), 13 (16), 14 (17) -pentaene-14-carboxamide (Compound 122)
Step 1 to a stirred solution of 5-bromo-13$l {3} -bromo-10-azatricyclododecane- (4), 1 (5), 2 (8), 3 (13), 6-penten-9-one (300 mg, 952.50. Mu. Mol) and 1-phenylethan-1-amine (173 mg,1.43 mmol) in a mixed solvent of HPLC grade t-BuOH (8 mL) and DMSO (0.8 mL) was added 3-diphenylphosphorylpropyl (diphenyl) phosphine (58.93 mg, 142.88. Mu. Mol), and the resulting solution was degassed with argon for 15 minutes. To this solution was added palladium diacetoxy (32.08 mg, 142.88. Mu. Mol), and the resulting reaction mixture was heated at 100℃under 60psi of CO gas for 12 hours. After completion, the reaction mixture was diluted with ethyl acetate (50 mL) and washed several times with water and brine solution. The organic phase was separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude reaction material was purified by column chromatography (100-200 mesh silica, 10-15% etoac/hexanes) to give 16-oxo-N- (1-phenylethyl) -19, 20-diazatricyclododecane-6 (11), 7 (12), 8 (13), 9 (19), 14-pentaene-12-carboxamide (40 mg,113.44 μmol,12% yield) as a colourless gum. LC-MS (ES) + ):m/z 318.3[M+H] + .
Step 2 sodium hydride (60% dispersion in mineral oil) (48.30 mg,1.26 mmol) was added portionwise to a cooled solution of 16-oxo-N- (1-phenylethyl) -19, 20-diazatricyclododecane-6, 8 (13), 9 (19), 11 (14), 12 (15) -penta-ene-12-carboxamide (40 mg, 126.05. Mu. Mol) in dry THF (5 mL) maintaining the temperature<5 ℃. After the addition, the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was then cooled again to 0deg.C and 3-bromopiperidine-2, 6-dione (121.01 mg, 630.24. Mu. Mol) was added in portions. The resulting solution was heated at 70℃for 1 hour. After complete exhaustion of 16-oxo-N- (1-phenylethyl) -19, 20-diazatricyclododecane-6, 8 (13), 9 (19), 11 (14), 12 (15) -pentaene-12-carboxamide, the reaction mixture was cooled to 0 ℃ and quenched by addition of ice-cold water (5 mL). The aqueous layer was extracted with ethyl acetate (3X 50 mL). The combined organics were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by PREP TLC to give 27- (2, 6-dioxo-3-piperidinyl) -20-oxo-N- (1-phenylethyl) -24, 27-diazatricyclododecane-6, 8 (15), 9 (24), 13 (16), 14 (17) -pentaene-14-carboxamide (compound 122,21mg,48.04 μmol,38% yield) as a yellow solid. 1 H NMR(400MHz,DMSO-d 6 )δ11.20(s,1H),11.06(d,,J＝7.76Hz,1H),9.01(d,J＝4.96Hz,1H),8.63(d,J＝7.32Hz,1H),8.25(d,J＝7.28Hz,1H),7.47-7.45(m,2H),7.36(t,J＝7.28Hz,3H),7.26(t,J＝7.28Hz,1H),5.50(dd,J＝11.84,3.48Hz,1H),5.32-5.28(m,1H),2.94(m,1H),2.76-2.65(m,2H),2.17-2.15(m,1H),1.59(d,J＝6.88Hz,3H)；LC-MS(ES + ):m/z 429.4[M+H] + .
EXAMPLE 53 Synthesis of 3- [18- (1-benzyl-4-fluoro-4-piperidinyl) -24-oxo-27, 30-diazatricyclododecane-5 (17), 6 (18), 7 (19), 8 (27), 20-pentaen-30-yl ] piperidine-2, 6-dione (compound 123)
Step 1 6-bromo-10, 11-diazatricyclododecane-, 2 (5), 3 (10), 4 (7), 6 (8) -penten-9-one (400 mg,1.61 mmol) was dissolved in anhydrous THF (10.0 mL) in a flame-dried round bottom flask under nitrogen atmosphere and the flask was cooled to-78 ℃. To this solution was added dropwise 1.8M di-n-butyl ether solution of phenyl lithium (683.64 mg,8.13mmol, 844.00. Mu.L), and the resulting reaction mixture was stirred at the same temperature for 30 minutes, followed by addition of butyl lithium (1.34M, 882.00. Mu.L) at-78 ℃. After the addition, the temperature was raised to-40 ℃ and the reaction mixture was stirred at the same temperature for an additional 30 minutes. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (319.99 mg,1.61 mmol) in dry THF (10.0 mL) was added at-78deg.C, and the reaction mixture was then warmed to room temperature and stirred at room temperature for 16 hours. After the reaction was completed, the mixture was quenched with ammonium chloride solution and diluted with ethyl acetate (100 mL). The combined organic phases were washed with water/brine and separated, dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the crude compound, which was purified by flash chromatography using 0-5% meoh-DCM to give 4-hydroxy-4- (16-oxo-20, 21-diazatricyclododecane-3, 5 (13), 6 (20), 11 (14), 12 (15) -pentaen-12-yl) piperidine-1-carboxylic acid tert-butyl ester (500 mg,947.45 μmol,59% yield) as a brown solid. LC-MS (ES) + ):m/z 370.4[M+H] + .
Step 2-4-hydroxy-4- (16-oxo-20, 21-diaza) to intimate agitation at-78deg.CTo a solution of tert-butyl tricyclododecane-3 (11), 4 (12), 5 (13), 6 (20), 14-pentaen-12-yl) piperidine-1-carboxylate (300 g,812.10 mmol) in anhydrous DCM (15.0 mL) was added dropwise N-ethyl-N- (trifluoro- $l {4} -sulfanyl) ethylamine (261.80 g,1.62mol,214.59 mL). After the addition was complete, the reaction mixture was warmed to room temperature and stirred for an additional 4 hours. After completion of the reaction, the reaction mixture was slowly poured into ice-cold NaHCO 3 (saturated) aqueous solution. The aqueous layer was extracted with DCM (3X 20 mL). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated and dried under vacuum to give crude 4-fluoro-4- (16-oxo-20, 21-diazatricyclododecane-3 (11), 4 (12), 5 (13), 6 (20), 14-pentaen-12-yl) piperidine-1-carboxylic acid tert-butyl ester (200 mg,301.56 μmol,4% yield) which was used in the next step without purification. LC-MS (ES) + ):m/z 372.4[M+H] + .
Step 3 4-fluoro-4- (16-oxo-20, 21-diazatricyclododecane-3 (11), 4 (12), 5 (13), 6 (20), 14-pentaen-12-yl) piperidine-1-carboxylic acid tert-butyl ester (200 mg, 301.56. Mu. Mol) in dioxane (4 mL) was added 4M dioxane-HCl (9.04 mmol,2.0 mL) at 0deg.C and the reaction mixture was stirred at room temperature for 4 hours. After completion, volatiles were removed under reduced pressure, the residue was washed with pentane/diethyl ether and dried in vacuo to give 9- (4-fluoro-4-piperidinyl) -15, 17-diazatricyclododecane- (8), 1 (9), 2 (10), 3 (15), 11-penten-13-one (109 mg,401.79 μmol), which was redissolved in anhydrous DCM (5.0 mL) and neutralized with triethylamine (pH-7). To this solution was added benzaldehyde (85.28 mg, 803.57. Mu. Mol, and 82.00. Mu.L), followed by acetic acid (48.25 mg, 803.57. Mu. Mol, and 45.96. Mu.L), and the resulting mixture was stirred at 60℃for 2 hours. The reaction mixture was then cooled to room temperature and sodium triacetoxyborohydride (425.77 mg,2.01 mmol) was added and stirring was continued for an additional 12 hours. After completion, volatiles were removed in vacuo and the resulting mixture was extracted with ethyl acetate (40 mL). The organic phase was washed with water/brine and separated, dried over sodium sulfate and concentrated under reduced pressure to give the crude product which was flash chromatographed (using 30-40% etoac/DCM as eluent) to give 16- (1-benzyl-4-fluoro-4-piperidinyl) -22, 23-diazatricyclododecane-5 (15), 6 (16), 7 (17), 8 (22), 18-pentaen-20-one (90 mg,209.18 μmol,52% yield) as a brown gum. LC-MS (ES) + ):m/z 362.2[M+H] + .
Step 4 sodium hydride (60% dispersion in mineral oil) (153.09 mg,4.00mmol,60% purity) was added portionwise to a cooled solution of 16- (1-benzyl-4-fluoro-4-piperidinyl) -22, 23-diazatricyclododecane-5 (15), 6 (16), 7 (17), 8 (22), 18-pentaen-20-one (57.76 mg, 159.82. Mu. Mol) in dry THF (5 mL) maintaining the temperature<5 ℃. After the addition, the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was then cooled again to 0 ℃ and 3-bromopiperidine-2, 6-dione (368.24 mg,1.92 mmol) was added thereto in portions. After the addition was completed, the resulting solution was heated at 70 ℃ for 1 hour. After completion, the reaction mixture was cooled to 0 ℃ and quenched by addition of ice-cold water (5 mL). The aqueous layer was extracted with ethyl acetate (3X 50 mL). The combined organics were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the crude product by PREP-TLC gave 3- [18- (1-benzyl-4-fluoro-4-piperidinyl) -24-oxo-27, 30-diazatricyclododecane-5 (17), 6 (18), 7 (19), 8 (27), 20-penten-30-yl]Piperidine-2, 6-dione (compound 123,26.3mg, 55.66. Mu. Mol,35% yield). 1 H NMR(400MHz,DMSO-d 6 )δ11.17(s,1H),8.92(d,J＝4.84Hz,1H),8.15(d,J＝7.36Hz,1H),8.05(d,J＝7.4Hz,1H),7.38-7.34(m,4H),7.29-7.24(m,2H),5.44(dd,J＝11.28,3.32Hz,1H),3.59(s,2H),3.28-3.19(m,2H),2.85-2.64(m,5H),2.49-41(m,2H),2.07(m,1H),1.88-1.82(m,2H)；LC-MS(ES + ):m/z 473.3[M+H] + .
3- [16- (1-benzyl-3-fluoro-azetidin-3-yl) -22-oxo-25, 28-diazatricyclododecane-5 (15), 6 (16), 7 (17), 8 (25), 18-pentaen-28-yl ] piperidine-2, 6-dione (compound 124)
Compound 124 was prepared essentially following the synthesis of compound 123.
1 H NMR(400MHz,DMSO-d 6 )δ11.15(s,1H),8.86(d,J＝4.84Hz,1H),8.14(d,J＝7.2Hz,1H),8.04-8.01(m,1H),7.35-7.32-7.29(m,4H),7.24-7.21(m,2H),5.45(dd,J＝12.68,5.16Hz,1H),4.10-4.02(m,2H),3.95-3.88(m,2H),3.77(s,2H),2.95-2.91(m,1H),2.76-2.48(m,2H),2.13-2.03(m,1H)；LC-MS(ES + ):m/z 445.24[M+H] + .
EXAMPLE 54 Synthesis of 3- [15- (1-Benzylazetidin-3-yl) -23-oxo-25, 28-diazatricyclododecane-5, 7 (17), 8 (25), 15 (19), 16 (18) -penten-28-yl ] piperidine-2, 6-dione (Compound 125)
Step 1 to a solution of freshly activated zinc powder (1.60 g,24.52 mmol) in DMAc (3 mL) was added chloro (trimethylsilane) (129.69. Mu.L, 1.02 mmol) and 1, 2-dibromoethane (123.28. Mu.L, 1.43 mmol) at room temperature. The resulting mixture was stirred at room temperature under an inert atmosphere for 10min. To the above mixture was added dropwise a solution of tert-butyl 3-iodoazetidine-1-carboxylate (5.79 g,20.44 mmol) in DMAc (15 mL) at room temperature and stirring was continued at room temperature for 2 hours. The reaction mixture was then added under inert conditions to degassed 6-bromo-10, 11-diazatricyclododecane-2 (5), 3 (10), 4 (7), 6 (8) -pent-9-one (509 mg,2.04 mmol), pdCl 2 (dppf) (74.77 mg, 102.18. Mu. Mol) and CuI (19.46 mg, 102.18. Mu. Mol) in DMAc (2 mL). The resulting reaction mixture was heated at 100℃for 16 hours. After completion, the reaction mixture was filtered through a short celite pad and washed with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (50% ethyl acetate-dichloromethane) to give tert-butyl 3- (15-oxo-18, 19-diazatricyclododecane-3, 5 (11), 6 (18), 9 (13), 10 (12) -pentaen-9-yl) azetidine-1-carboxylate (350 mg,1.08mmol,53% yield). LC-MS (ES) + ):m/z 326.2[M+H] + .
Step 2 to a stirred solution of 3- (15-oxo-18, 19-diazatricyclododecane-3, 5 (11), 6 (18), 9 (13), 10 (12) -pentaen-9-yl) azetidine-1-carboxylic acid tert-butyl ester (350 mg,1.08 mmol) in DCM (3 mL) was added dropwise trifluoroacetic acid (3.50 mL,45.43 mmol) at 0deg.C. The resulting mixture was warmed to room temperature and stirred for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure and triturated with n-pentane to give 6- (azetidin-3-yl) -13, 15-diazatricyclododeca-neAlkane-, 2 (8), 3 (13), 6 (10), 7 (9) -penten-12-one trifluoroacetate salt (200 mg, 589.50. Mu. Mol,55% yield). LC-MS (ES) + ):m/z 226.26[M+H] + .
Step 3 benzyl chloride (50.88. Mu.L, 442.13. Mu.L) and DIPEA (154.02. Mu.L, 884.25. Mu. Mol) were added to a stirred solution of 6- (azetidin-3-yl) -13, 15-diazatricyclododecane-, 2 (8), 3 (13), 6 (10), 7 (9) -penten-12-one (200 mg, 589.50. Mu. Mol) (150 mg, 442.13. Mu. Mol) in MeCN (15 mL) at 0deg.C. The resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was concentrated, diluted with 5% meoh/DCM and washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 8- (1-benzyl azetidin-3-yl) pyrrolo [2,3,4-de]Quinolin-5 (4H) -one (70 mg, 221.07. Mu. Mol,50% yield) was used in the next step without any further purification. LC-MS (ES) + ):m/z 316.2[M+H] + .
Step 4 to a stirred solution of 13- (1-benzyl azetidin-3-yl) -20, 21-diazatricyclododecane-5, 7 (15), 8 (20), 13 (17), 14 (16) -pentaen-19-one (70 mg, 221.96. Mu. Mol) in DMF (5 mL) in a sealed tube at 0deg.C was added lithium tert-butoxide (71.08 mg, 887.85. Mu. Mol) followed by 3-bromopiperidine-2, 6-dione (85.24 mg, 443.93. Mu. Mol). The resulting mixture was heated at 80℃for 20 hours. After completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification of the crude product by reverse phase preparative HPLC gave 3- [15- (1-benzyl azetidin-3-yl) -23-oxo-25, 28-diazatricyclododecane-5, 7 (17), 8 (25), 15 (19), 16 (18) -penten-28-yl]Piperidine-2, 6-dione (Compound 125,3.25mg, 6.56. Mu. Mol,3% yield). LC-MS (ES) + ):m/z 427.32[M+H] + .
EXAMPLE 55 Synthesis of 3- [17- (1-benzyl-4-piperidinyl) -25-oxo-27, 30-diazatricyclododecane-5 (17), 6 (18), 7 (19), 8 (27), 20-penten-30-yl ] piperidine-2, 6-dione (Compound 126)
Step 1, the direction isTo a degassed solution of 6-bromo-10, 11-diazatricyclododecane- (4), 1 (6), 2 (5), 3 (10), 7-pentaen-9-one (580.0 mg,2.33 mmol) and 4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.08 g,3.49 mmol) in dioxane-water (4:1, v/v,10 mL) was added cyclopentyl (diphenyl) phosphine; dichloromethane; palladium dichloride; iron (190.17 mg, 232.87. Mu. Mol) and potassium carbonate (965.53 mg,6.99 mmol) and the resulting reaction mixture was heated at 100℃for 16 hours. After completion, the reaction mixture was concentrated in vacuo and the crude product was purified by column chromatography (10-20% etoac/DCM) to give 4- (17-oxo-20, 21-diazatricyclododecane-3 (11), 4 (12), 5 (13), 6 (20), 14-pentaen-12-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3) (600 mg,1.67mmol,72% yield) as an off-white solid. LC-MS (ES) + ):m/z 352.2[M+H] + .
Step 2A solution of 4- (18-oxo-21, 22-diazatricyclododecane-3 (12), 4 (13), 5 (14), 6 (21), 15-pentaen-13-yl) -3, 6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (500 mg,1.42 mmol) in methanol (2 mL) was degassed with argon for 10 minutes, followed by the addition of 10% Pd/C (91.74 mg, 86.20. Mu. Mol). The resulting reaction mixture was hydrogenated at balloon pressure for 30 minutes at room temperature. The reaction mixture was then filtered through a pad of celite and washed with 10% meoh/DCM. The filtrate was evaporated under reduced pressure and the crude product was purified by flash column chromatography (50-60% etoac/hexanes) to give 4- (18-oxo-21, 22-diazatricyclododecane-3 (12), 4 (13), 5 (14), 6 (21), 15-pentaen-12-yl) piperidine-1-carboxylic acid tert-butyl ester (480 mg,84% yield) as a brown solid. LC-MS (ES) + ):m/z 354.34[M+H] + .
Step 3 4- (17-oxo-20, 21-diazatricyclododecane-3 (11), 4 (12), 5 (13), 6 (20), 14-pentaen-11-yl) piperidine-1-carboxylic acid tert-butyl ester (470 mg,1.33 mmol) was added 4M dioxane-HCl (5.32 mmol,0.5 mL) at 0deg.C and stirred at room temperature for 3 hours. After completion of the reaction, volatiles were removed under reduced pressure to give 8- (4-piperidinyl) -15, 17-diazatricyclododecane- (8), 1 (9), 2 (10), 3 (15), 11-penten-14-one (220 mg,781.69 μmol,59% yield), which was used in the next step without purification. LC-MS (ES) + ):m/z 254.2[M+H] + .
Step 4, stirring to 8- (1-Chloro-4-piperidinyl) -15, 16-diazatricyclododecane- (8), 1 (9), 2 (10), 3 (15), 11-pentaen-14-one (170 mg, 586.69. Mu. Mol) to a suspension of DCM (5.0 mL) and methanol (2.0 mL) was added triethylamine (pH-7). Benzaldehyde (124.52 mg,1.17mmol, 119.73. Mu.L) and acetic acid (70.46 mg,1.17mmol, 67.11. Mu.L) were then added under a nitrogen atmosphere. The resulting solution was stirred at room temperature for 4 hours, then sodium triacetoxyborohydride (621.72 mg,2.93 mmol) was added in portions at 0 ℃. The reaction mixture was heated at 60 ℃ for a further 12 hours. After completion, the reaction mixture was diluted with 20% meoh-DCM (30 mL) and washed with saturated sodium bicarbonate solution, water and brine. The organic phase was separated, dried over sodium sulfate and concentrated to give the crude product which was purified by flash column (0-10% meoh-DCM) to give 15- (1-benzyl-4-piperidinyl) -22, 23-diazatricyclododecane-5 (15), 6 (16), 7 (17), 8 (22), 18-pentaen-21-one (80 mg,151.42 μmol,26% yield). LC-MS (ES) + ):m/z 344.28[M+H] + .
Step 5 sodium hydride (60% dispersion in mineral oil) (89.26 mg,2.33 mmol) was added portionwise to a cooled solution of 15- (1-benzyl-4-piperidinyl) -22, 23-diazatricyclododecane-5 (15), 6 (16), 7 (17), 8 (22), 18-penta-en-21-one (80 mg, 232.95. Mu. Mol) in dry THF (5 mL) maintaining the temperature <5 ℃. After the addition, the resulting mixture was stirred at room temperature for 15 minutes. The reaction mixture was then cooled to 0deg.C and 3-bromopiperidine-2, 6-dione (223.64 mg,1.16 mmol) was added in portions and the mixture was heated at 70deg.C for 1 hour. After completion, the reaction mixture was cooled to 0 ℃ and quenched by addition of ice-cold water (5 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by PREP-TLC to give 3- [17- (1-benzyl-4-piperidinyl) -25-oxo-27, 30-diazatricyclododecane-5 (17), 6 (18), 7 (19), 8 (27), 20-penten-30-yl as a yellow solid]Piperidine-2, 6-dione (Compound 126,21.3mg, 46.86. Mu. Mol,20% yield). LC-MS (ES) + ):m/z455.33[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ11.15(s,1H),8.86(d,J＝4.76Hz,1H),8.08(d,J＝7.32Hz,1H),7.86(d,J＝7.36Hz,1H),7.35-7.32(m,4H),7.27-7.24(m,1H),7.21(d,J＝4.8Hz,1H),5.44(dd,J＝12.8,5.08Hz,1H),3.81-3.55(m,1H),3.38(s,2H),3.0-2.89(m,3H),2.75-2.63(m,2H),2.18-2.10(m,3H),1.94-1.87(m,4H).
EXAMPLE 56 Synthesis of 3- [14- [1- [ (2-methoxypyrimidin-5-yl) methyl ] -4-piperidinyl ] -24-oxo-26,31-diazatricyclododecane-1 (14), 2 (15), 3 (16), 4 (26), 18-pentaen-31-yl ] piperidine-2, 6-dione (Compound 127)
To 3- [ 18-oxo-10- (4-piperidinyl) -20, 23-diazatricyclododecane- (10), 1 (11), 2 (12), 3 (20), 13-penten-23-yl]To a solution of piperidine-2, 6-dione (80 mg, 219.54. Mu. Mol) and 2-methoxypyrimidine-5-carbaldehyde (30.32 mg, 219.54. Mu. Mol) in anhydrous THF (4 mL) was added dibutyltin dichloride (100 mg, 73.57. Mu.L, 329.31. Mu. Mol) in portions, and the reaction mixture was heated at 70℃for 1 hour. Subsequently, the reaction mixture was cooled to room temperature and phenylsilane (28.51 mg,32.51 μl,263.45 μmol) was added. The mixture was heated in a sealed vial at 70 ℃ for an additional 12 hours. After completion, the reaction mixture was cooled to 0 ℃ and quenched by addition of ice-cold water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organics were separated, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by PREP-TLC to give 3- [14- [1- [ (2-methoxypyrimidin-5-yl) methyl ] as an off-white solid ]-4-piperidinyl]-24-oxo-26,31-diazatricyclododecane-1 (14), 2 (15), 3 (16), 4 (26), 18-pentaen-31-yl]Piperidine-2, 6-dione (Compound 127,8.5mg, 17.44. Mu. Mol,8% yield). LC-MS (ES) + ):m/z487.2[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ11.15(s,1H),8.86(d,J＝4.68Hz,1H),8.55(s,2H),8.08(d,J＝7.28Hz,1H),7.84(d,J＝7.4Hz,1H),7.21(d,J＝4.76Hz,1H),5.43(m,1H),3.91(s,3H),3.79(m,1H),3.53(s,2H),2.99-2.97(br m,6H),2.19-2.16(m,3H),1.90(m,3H).
EXAMPLE 57 Synthesis of 3- [21- [1- [ (3-morpholinosulfonylphenyl) methyl ] -4-piperidinyl ] -29-oxo-31, 35-diazatricyclododecane-3 (21), 4 (22), 5 (23), 6 (31), 24-penten-35-yl ] piperidine-2, 6-dione (Compound 128)
Step 1 to a stirred solution of tert-butyl 4- (17-oxo-20, 21-diazatricyclododecane-3, 5 (13), 6 (20), 11 (15), 12 (14) -pentaen-11-yl) piperidine-1-carboxylate (100 mg, 282.95. Mu. Mol) in DMF (5 mL) was added lithium tert-butoxide (90.61 mg,1.13 mmol) followed by 3-bromopiperidine-2, 6-dione (108.66 mg, 565.91. Mu. Mol) at 0deg.C. The resulting reaction mixture was heated at 90℃for 16 hours. After completion, the reaction mixture was taken up with saturated NH 4 The Cl solution was quenched and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by combi-flash column chromatography (50% etoac/DCM) to give 4- [28- (2, 6-dioxo-3-piperidinyl) -21-oxo-25, 28-diazatricyclododecane-3, 5 (15), 6 (25), 13 (17), 14 (16) -penten-13-yl]Tert-butyl piperidine-1-carboxylate (25 mg, 38.75. Mu. Mol,14% yield). LC-MS (ES) + ):m/z 465[M+H] + .
Step 2 4- [28- (2, 6-dioxo-3-piperidyl) -21-oxo-25, 28-diazatricyclododecane-3, 5 (15), 6 (25), 13 (17), 14 (16) -penten-13-yl with stirring at 0deg.C]To a solution of tert-butyl piperidine-1-carboxylate (25 mg, 53.82. Mu. Mol) in 1, 4-dioxane (0.5 mL) was added dioxane-HCl (4M, 30. Mu.L) dropwise. The reaction mixture was stirred at the same temperature for 3 hours. After completion, the mixture was evaporated to dryness to give 3- [ 18-oxo-10- (4-piperidinyl) -20, 23-diazatricyclododecane-, 2 (12), 3 (20), 10 (14), 11 (13) -penten-23-yl]Piperidine-2, 6-dione hydrochloride (15 mg crude, 37.42. Mu. Mol,70% yield). LC-MS (ES) + ):m/z 365[M+H] + .
Step 3 to stirring 3- [ 18-oxo-10- (4-piperidinyl) -20, 23-diazatricyclododecane-, 2 (12), 3 (20), 10 (14), 11 (13) -penten-23-yl]To a solution of piperidine-2, 6-dione hydrochloride (15 mg, 37.42. Mu. Mol), 3-morpholinosulfonylbenzaldehyde (9.55 mg, 37.42. Mu. Mol) in THF (3 mL) was added dibutyltin dichloride (13.64 mg, 44.90. Mu. Mol, 10.03. Mu.L) and Et 3 N (7.57 mg, 74.84. Mu. Mol, 10.43. Mu.L) and the reaction mixture was stirred at 60℃for 1 hour. The mixture was cooled to ambient temperature and phenylsilane (6.07 mg, 56.13. Mu. Mol) was added. The resulting solution was heated at 80℃for a further 12 hours. The crude product was purified by reverse phase prep. HPLC to give 3- [21- [1- [ (3-morpholinosulfonylphenyl) methyl ]]-4-piperidinyl]-29-oxo-31, 35-diazatricyclododecane-3 (21), 4 (22), 5 (23), 6 (31), 24-pentaen-35-yl]Piperidine-2, 6-dione (Compound 128,2.94mg, 4.69. Mu. Mol,13% yield). LC-MS (ES) + ):m/z 604[M+H] + . 1 H NMR(400MHz,DMSO-d 6 ) δ11.16 (s, 1H), 8.86 (d, j=8 hz, 1H), 8.10 (t, j=8 hz, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 7.64 (s, 1H), 7.22 (d, j=8 hz, 1H), 5.44 (dd, j=12 hz,4hz, 1H), 4.55 (s, 1H), 3.85 (s, 1H), 3.69 (s, 1H), 3.63 (s, 4H), 2.97-2.94 (m, 2H), 2.88 (s, 4H), 2.75-2.63 (m, 2H), 2.32-2.24 (m, 2H), 2.13-2.10 (m, 1H), 1.90 (s, 3H), two aliphatic protons are not visualized.
EXAMPLE 58 Synthesis of 29- (2, 6-dioxo-3-piperidyl) -N- (2-methyl-1-phenyl-propyl) -21-oxo-26, 29-diazatricyclododecane-7, 9 (16), 10 (26), 14 (17), 15 (18) -pentaene-15-carboxamide (Compound 129)
Step 1 to a solution of 6-bromo-10, 11-diazatricyclododecane-, 2 (5), 3 (10), 4 (7), 6 (8) -penten-9-one (0.5 g,2.01 mmol) in THF (5 mL) was added NaH (60% dispersion in mineral oil) (92.31 mg,4.02mmol,6.69 mL) at room temperature, and the resulting solution was heated at 60 ℃ for 1 hour. In another flask, a stirred solution of 3-bromopiperidine-2, 6-dione (578.20 mg,3.01 mmol) in THF (5 mL) was heated at 60 ℃ and the foregoing mixture was slowly added to the solution. Heating was continued at the same temperature for another 16 hours. After completion, the reaction mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with water, saturated brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by combi-flash column chromatography (50% ethyl acetate-DCM) to give 3- (8-bromo-13-oxo-15, 17-diazatricyclododecane-, 2 (7), 3 (15), 6 (9), 8 (10) -penten-17-yl) piperidine-2, 6-dione (100 mg,263.77 μmol,13% yield). LC-MS (ES) + ):m/z360[M+H] + .
Step 2 to 3- (8-bromo-13-oxo-15, 17-diazaTricyclododecane-, 2 (7), 3 (15), 6 (9), 8 (10) -penten-17-yl) piperidine-2, 6-dione (50 mg, 138.83. Mu. Mol) in DMF (0.5 mL) was added triethylamine (56.19 mg, 555.31. Mu. Mol, 77.40. Mu.L) and 2-methyl-1-phenyl-propan-1-amine (31.08 mg, 208.24. Mu. Mol). The resulting solution was degassed and backfilled with argon for 5 minutes, then xanthene (16.07 mg,27.77 μmol) and Pd (OAc) were added 2 (12.47 mg, 55.53. Mu. Mol). The mixture was again degassed and backfilled with argon for 2 minutes. The reaction mixture was purged with a carbon monoxide filled balloon and heated at 80 ℃ under this atmosphere for 16 hours. After the completion of the reaction, the reaction mixture was purified by reverse phase preparation purification to give 29- (2, 6-dioxo-3-piperidinyl) -N- (2-methyl-1-phenyl-propyl) -21-oxo-26, 29-diazatricyclododecane-7, 9 (16), 10 (26), 14 (17), 15 (18) -pentaene-15-carboxamide (compound 129,2.43mg,5.02 μmol,4% yield). LC-MS (ES) + ):m/z 457[M+H] + . 1 H NMR(400MHz,DMSO-d 6 )δ11.28(s,1H),11.16(br.s,1H),9.08(d,J＝8Hz,1H),8.83(d,J＝8Hz,1H),8.24(d,J＝8Hz,1H),7.40-7.32(m,5H),7.26(s,1H),5.51(dd,J＝12Hz,4Hz,1H),5.07(q,J＝8Hz,1H),2.94-2.90(m,1H),2.78-2.73(m,2H),2.68(d,J＝16Hz,1H),2.22-2.15(m,2H),1.23(s,2H),0.99-0.94(m,6H).
Compound 130-compound 133 was prepared essentially following the synthesis of compound 129.
28- (2, 6-dioxo-3-piperidyl) -N- [1- (2-methoxyphenyl) ethyl ] -21-oxo-25, 28-diazatricyclododecane-6, 8 (15), 9 (25), 12 (17), 14 (18) -pentaene-14-carboxamide (Compound 130)
LC-MS(ES + ):m/z 459.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.23(d,J＝8.3Hz,1H),9.06(d,J＝5.0Hz,1H),8.65(d,J＝7.3Hz,1H),8.25(d,J＝7.3Hz,1H),7.37-7.34(m,2H),7.26(dt,J＝6.6,1.4Hz,1H),7.05(d,J＝8.1Hz,1H),6.91(t,J＝7.3Hz,1H),5.53-5.48(m,1H),3.92(s,3H),2.91-2.85(m,1H),2.77-2.64(m,2H),2.18-2.16(m,1H),1.53(d,J＝6.9Hz,3H).
27- (2, 6-dioxo-3-piperidinyl) -19-oxo-N- (2, 2-trifluoro-1-phenyl-ethyl) -24, 27-diazatricyclododecane-5, 7 (14), 8 (24), 12 (15), 13 (16) -pentaene-13-carboxamide (Compound 131)
LC-MS(ES + ):m/z 483.2[M+H] + .
N- (1-cyclohexylethyl) -27- (2, 6-dioxo-3-piperidinyl) -20-oxo-24, 27-diazatricyclododecane-1, 3 (14), 4 (24), 12 (15), 13 (16) -pentaene-13-carboxamide (Compound 132)
LC-MS(ES + ):m/z 435.3[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ11.20(s,1H),10.59(d,J＝8.5Hz,1H),8.99(d,J＝5.0Hz,1H),8.65(d,J＝7.3Hz,1H),8.25(d,J＝7.3Hz,1H),7.34(dd,J＝4.9,1.3Hz,1H),5.51-5.47(m,1H),4.08-4.03(m,1H),2.93-2.65(m,3H),2.16-2.13(m,1H),1.86-1.52(m,6H),1.24-1.06(m,4H),1.22(d,J＝6.7Hz,3H)
22- (2, 6-dioxo-3-piperidyl) -N-isopropyl-15-oxo-19, 22-diazatricyclododecane-2, 4 (10), 5 (19), 8 (11), 9 (12) -penta-ene-9-carboxamide (Compound 133)
LC-MS(ES + ):m/z 367.2[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )δ 11,20(s,1H),10.47(d,J＝7.36Hz,1H),8.98(d,J＝4.92Hz,1H),8.65(d,J＝7.36Hz,1H),8.25(d,J＝Hz,1H),7.35(d,J＝7.32Hz,1H),5.55-5.45(m,1H),4.21-4.20(m,1H),3.21-2.90(m,1H),2.78-2.61(m,2H),2.19-2.10(m,1H),1.29(d,J＝6.56Hz,6H).
EXAMPLE 59 Synthesis of N2- (2, 6-dioxo-3-piperidyl) -N5- (1-phenylethyl) pyridine-2, 5-carboxamide (Compound 134)
Step 1 to a stirred solution of 6-methoxycarbonylpyridine-3-carboxylic acid (500 mg,2.76 mmol) in DCM (10 mL) was added N-and-N-isopropyl-propan-2-amine (713.48 mg,5.52mmol, 961.56. Mu.L) and HATU (1.06 g,2.76 mmol) and the reaction mixture was stirred at room temperature for 15 min. 1-Phenylethylamine (334.48 mg,2.76mmol, 353.95. Mu.L) was added to the solution, and the resulting mixture was stirred for another 16 hours. After the completion of the reaction, the reaction mixture was diluted with water, and the separated organic layer was washed with water, saturated brine solution, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude product was purified by combi-flash column chromatography (50% etoac/hexanes) to give methyl 5- (1-phenylethylcarbamoyl) pyridine-2-carboxylate (500 mg,1.60mmol,58% yield). LC-MS (ES) + ):m/z 285[M+H] + .
Step 2 to stirred methyl 5- (1-phenylethylcarbamoyl) pyridine-2-carboxylate (250 mg, 879.32. Mu. Mol) in THF-MeOH-H at 10 ℃ 2 LiOH.H was added to a solution in a mixture of O (3.5 mL, 4:2:1) 2 O (55.35 mg,1.32 mmol). The resulting mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was concentrated in vacuo, diluted with water, and washed with ethyl acetate. The organic layer was discarded, the aqueous layer was cooled and acidified with 1N HCl until pH 2. It was then re-extracted with ethyl acetate and the organic phase was dried over anhydrous sodium sulfate and concentrated in vacuo to give 5- (1-phenylethylcarbamoyl) pyridine-2-carboxylic acid (160 mg, 561.19. Mu. Mol,64% yield) LC-MS (ES) + ):m/z 271[M+H] + .
Step 3 to a stirred solution of 5- (1-phenylethylcarbamoyl) pyridine-2-carboxylic acid (100 mg, 369.98. Mu. Mol) in DMF (3 mL) was added HATU (141.42 mg, 369.98. Mu. Mol) and DIPEA (95.64 mg, 739.97. Mu. Mol, 128.89. Mu.L), and the mixture was stirred at room temperature for 15 minutes. Subsequently, 3-amino-2, 6-piperidinedione (47.41 mg, 369.98. Mu. Mol) was added and the resulting mixture was stirred at room temperature for 16 hours. After the reaction is completedThe reaction mixture was purified by reverse phase prep HPLC to give N2- (2, 6-dioxo-3-piperidinyl) -N5- (1-phenylethyl) pyridine-2, 5-dicarboxamide (compound 134,40.17mg,105.60 μmol,29% yield). LC-MS (ES) + ):m/z 381[M+H] + . 1 H NMR(400MHz,DMSO-d 6 ) δ10.86 (s, 1H), 9.18 (d, j=8 hz, 2H), 9.07 (s, 1H), 8.45 (d, j=8 hz, 1H), 8.15 (d, j=8 hz, 1H), 7.41 (d, j=8 hz, 2H), 7.34 (t, j=8 hz, 2H), 7.25 (d, j=8 hz, 1H), 5.19 (t, j=8 hz, 1H), 4.81 (m, 1H), 2.80 (d, j=16 hz, 1H), 2.24 (d, j=8 hz, 1H), 2.01 (m, 1H), 1.50 (d, j=8 hz, 3H), a proton is combined with the residual solvent peak.
Example 60
3- (8- (4, 6-dimethylpyrimidin-2-yl) -5-oxopyrrolo [2,3,4-de ] quinolin-4 (5H) -yl) piperidine-2, 6-dione (compound 135)
Compound 135 was prepared essentially following the synthesis of compound 106 in example 44, but using 14-bromo-19- [ (4-methoxyphenyl) methyl ] -18, 19-diazatricyclododecane-5 (12), 6 (14), 7 (13), 8 (18), 15-pentaen-17-one as starting material in step 2.
Example 61IKZF2 degradation assay
HiBit method
Material
RPMI 1640 medium without phenol red and Fetal Bovine Serum (FBS) was purchased from Gibco (Grand Island, NY, USA).HiBiT Lytic assay System is available from Promega (Madison, wis., USA). Jurkat.21 (IKZF 2-HiBiT) cell lines endogenously expressing IKZF2 with a HiBiT fusion tag via CRISPR were purchased from Synthesis (Menlo Park, calif., USA). Cell culture flasks and 384-well microplates were obtained from VWR (Radnor, PA, USA).
IKZF2 degradation assay
IKZF2 degradation is based on use HiBiT LyticThe determination kit is used for determining the quantification of the luminous signals. Test compounds were added to 384 well plates at the highest concentration of 10 μm and 11-point, semilog titrations were performed in duplicate. Jurkat.216 cells were added to 384 well plates at a cell density of 5000 cells per well. The plates were incubated at 37℃with 5% CO 2 Hold down for 6 or 24 hours. The cells treated in the absence of test compound were negative controls and were notCells of the HiBiT Lytic reagent are positive controls. After incubation for 6 or 24 hours, the mixture is thenHiBiT Lytic reagent is added to the cells. In EnVision TM Luminescence was obtained on a multi-tag reader (PerkinElmer, santa Clara, CA, USA).
Example 62 GSPT1 degradation assay
HiBit method
Material
DMEM phenol red free medium and Fetal Bovine Serum (FBS) were purchased from Gibco (Grand Island, NY, USA).HiBiT Lytic assay System is available from Promega (Madison, wis., USA). Homemade produced a 293t.114 (HiBiT-GSPT 1) cell line endogenously expressing IKZF2 with a HiBiT fusion tag via CRISPR. Cell culture flasks and 384-well microplates were obtained from VWR (Radnor, PA, USA).
GSPT1 degradation analysis
GSPT1 degradation is based on usageThe HiBiT Lytic assay kit is used for quantifying the luminous signals. Test compounds were added to 384 well plates at a maximum concentration of 10 μm and 11-point, semilog titrations were performed in duplicate. 293T.114 cells were added to 384 well plates at a cell density of 6000 cells per well. The plates were incubated at 37℃with 5% CO 2 Hold down for 6 hours. The cells treated in the absence of test compound are negative controls and are free of +.>Cells of the HiBiT Lytic reagent are positive controls. After 6 hours of incubation, will +.>HiBiT Lytic assay reagents were added to the indicated wells. In EnVision TM Luminescence was obtained on a multi-tag reader (PerkinElmer, santa Clara, CA, USA).
TABLE 1
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As used in the above table, for IC 50 Value of<500nM＝+++,500-10,000nM＝++,
>10,000nM＝+
For Emax value <) 45% = ++++, 45% = + ++ + +,60-95% = +++, 95% = + table 2
As used in the above table, for IC 50 Value of<500nM＝+++,500-10,000nM＝++,
>10,000nM＝+
For Emax value <) 45% = + ++ + +,45-60% = ++++, no.) = + type ++
All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the invention as defined in the claims and the embodiments.

Claims (121)

1. A compound of the formula:
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 is that
Q 1 Is CH or N;
x is selected from the group consisting of bond, alkyl, aliphatic, heterocyclic (which may be bonded through C and/or N in the ring), aryl, heteroaryl, bicyclic, -NR 27 -、-NR 10 -、-CR 40 R 41 -、-O-、-C(O)-、-C(NR 27 )-、-C(S)-、-S(O)-、-S(O) 2 -and-S-; where the valences permit formation of stable compounds, each of which is optionally substituted with 1, 2, 3 or 4 groups independently selected from non-hydrogen R 40 Is substituted by a substituent of (a);
R 15 、R 16 and R is 17 Independently at each occurrence selected from the group consisting of bond, alkyl, -C (O) -, -C (O) O-, -OC (O) -, -SO 2 -、-S(O)-、-C(S)-、-C(O)NR 27 -、-NR 27 C(O)-、-O-、-S-、-NR 27 -、-NR 10 -、-C(R 40 R 41 ) -, bicyclic, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, cycloalkyl, heteroaliphatic, and heteroaryl; where the valences permit to form stable compounds, each of which is optionally substituted with 1, 2, 3 or 4 groups of compounds independently selected from R 40 Is substituted by a substituent of (a); and wherein R is 15 、R 16 And R is 17 Not more than two of which are selected as keys;
R 18 selected from hydrogen, halogen, cyano, -C (O) R 27 、-C(O)OR 27 Alkyl, -C (O) NR 10 R 27 、-NR 27 C(O)R 27 、–NR 10 R 27 、-OR 27 、-SR 27 Alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, aliphatic, heteroaliphatic, and heteroaryl; where the valences permit to form stable compounds, each of which is optionally substituted with 1, 2, 3 or 4 groups of compounds independently selected from R 40 Is substituted by a substituent of (a); and therein X, R 15 、R 16 、R 17 And R is 18 As known to those skilled in the art, provides R that is stable under ambient use conditions and desired shelf life 1 Selecting a combination of parts;
R 27 independently at each occurrence, selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, heterocycle, cycloalkyl, aliphatic, and heteroaliphatic;
R 40 independently at each occurrence selected from hydrogen, aliphatic, heteroaliphatic, cyano, nitro, alkyl, halo, haloalkyl, -OR 10 、-SR 10 、-S(O)R 12 、-SO 2 R 12 and-NR 10 R 11 ；
R 41 Is aliphatic, aryl, heteroaryl, or hydrogen;
a is selected from:
n is 0, 1 or 2;
X 3 is NR 10 、NR 6’ O or S;
q is CR 7 Or N;
R 3 is hydrogen, alkyl, halogen or haloalkyl;
or R is 3 And R is 6 To form a 1 or 2 carbon linkage;
or R is 3 And R is 4 To form a 1, 2, 3 or 4 carbon linkage;
or R is 3 And R is equal to 3 Adjacent R 4 The groups combine to form a double bond.
R 4 And R is 5 Independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 、-SR 10 、-S(O)R 12 、-SO 2 R 12 and-NR 10 R 11 ；
R 6 And R is 7 Independently selected from hydrogen, alkyl, halogen, haloalkyl, -OR 10 、-SR 10 、-S(O)R 12 、-SO 2 R 12 and-NR 10 R 11 ；
R 6 ' is hydrogen, alkyl or haloalkyl;
or R is 3 And R is 6 ' combine to form a 1 or 2 carbon linkage.
Each R 10 And R is 11 Independently selected from hydrogen, aliphatic, alkyl, haloalkyl, heterocycle, aryl, heteroaryl, -C (O) R 12 、-S(O)R 12 and-SO 2 R 12 ；
Each R 12 Independently selected from hydrogen, alkyl, haloalkyl, heterocycle, aryl, heteroaryl, -NR 13 R 14 And OR 13 The method comprises the steps of carrying out a first treatment on the surface of the And
r in each case 13 And R is 14 Independently selected from hydrogen, alkyl and haloalkyl.
2. The compound of claim 1, having the formula:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1, having the formula:
or a pharmaceutically acceptable salt thereof.
4. A compound according to any one of claims 1-3, wherein a is
5. A compound according to any one of claims 1-3, wherein a is
6. A compound according to any one of claims 1-3, wherein a is
7. A compound according to any one of claims 1-3, wherein a is
8. A compound according to any one of claims 1-3, wherein a is
9. A compound according to any one of claims 1-3, wherein a is
10. The compound according to any one of claims 1-9, wherein n is 1.
11. The compound of claim 10, wherein R 4 Is hydrogen.
12. The compound of claim 10, wherein R 4 Is an alkyl group.
13. The compound of claim 10, wherein R 4 Is halogen.
14. The compound of any one of claims 1-4 or 6-10, wherein R 3 And R is 4 Combine to form a 1, 2, 3, or 4 carbon linkage.
15. The compound of any one of claims 1-9, wherein n is 0.
16. The compound according to any one of claims 1-9, wherein n is 2.
17. A compound according to any one of claims 1-3, wherein a is
18. A compound according to any one of claims 1-3, wherein a is
19. A compound according to any one of claims 1-3, wherein a is
20. The compound of any one of claims 17-19, wherein R 3 Is hydrogen.
21. The compound of any one of claims 17-19, wherein R 3 Is an alkyl group.
22. The compound of any one of claims 17-19, wherein R 3 Is a haloalkyl group.
23. The compound of any one of claims 17-19, wherein R 3 Is methyl.
24. A compound according to any one of claims 1-3, wherein a is
25. The compound of claim 18 or claim 24, wherein Q is N.
26. The compound of claim 18 or claim 24, wherein Q is CH.
27. A compound according to any one of claims 1-3, wherein a is
28. A compound according to any one of claims 1-3, wherein a is
29. A compound according to any one of claims 1-3, wherein a is
30. The compound of claim 28 or claim 29, wherein R 6 Is hydrogen.
31. The compound of claim 28 or claim 29, wherein R 6 Is an alkyl group.
32. The compound of claim 28 or claim 29, wherein R 6 Is a haloalkyl group.
33. The compound of claim 28 or claim 29, wherein R 6 Is halogen.
34. The compound of claim 28 or claim 29, wherein R 6 Is NR 10 R 11 。
35. The compound of claim 28 or claim 29, wherein R 6 Is OR (OR) 10 。
36. The compound of any one of claims 27-35, wherein R 5 Is hydrogen.
37. The compound of any one of claims 27-35, wherein R 5 Is an alkyl group.
38. The compound of any one of claims 27-35, wherein R 5 Is a haloalkyl group.
39. The compound of any one of claims 27-35, wherein R 5 Is halogen.
40. A compound according to any one of claims 1-3, wherein a is
41. The compound of any one of claims 27-40, wherein R 7 Is hydrogen.
42. The compound of any one of claims 27-40, wherein R 7 Is an alkyl group.
43. The compound of any one of claims 27-40, wherein R 7 Is a haloalkyl group.
44. The compound of any one of claims 27-40, wherein R 7 Is halogen.
45. A compound according to any one of claims 1-44, wherein X is alkyl.
46. The compound of any one of claims 1-44, wherein X is a heterocycle.
47. The compound of any one of claims 1-44, wherein X is aryl.
48. The compound of any one of claims 1-44, wherein X is heteroaryl.
49. The compound of any one of claims 1-44, wherein X is a bicyclic ring.
50. A compound according to any one of claims 1-44, wherein X is-NR 27 -。
51. A compound according to any one of claims 1-44, wherein X is-NR 10 -。
52. A compound according to any one of claims 1-44, wherein X is-CR 40 R 41 -。
53. The compound of any one of claims 1-44, wherein X is-O-.
54. A compound according to any one of claims 1-44, wherein X is-C (O) -.
55. A compound according to any one of claims 1-44, wherein X is-C (NR 27 )-。
56. A compound according to any one of claims 1-44, wherein X is-C (S) -.
57. A compound according to any one of claims 1-44, wherein X is-S (O) -.
58. A compound according to any one of claims 1-44, wherein X is-S (O) 2 -。
59. The compound of any one of claims 1-44, wherein X is-S-.
60. A compound according to any one of claims 1-44, wherein X is a bond.
61. The compound of any one of claims 1-60, wherein R 15 Is a key.
62. The compound of any one of claims 1-60, wherein R 15 Is an alkyl group.
63. The compound of any one of claims 1-60, wherein R 15 Is a heterocyclic group.
64. The compound of any one of claims 1-60, wherein R 15 Is aryl.
65. The compound of any one of claims 1-60, wherein R 15 Is heteroaryl.
66. The compound of any one of claims 1-60, wherein R 15 Is a bicyclic ring.
67. The compound of any one of claims 1-60, wherein R 15 Is a haloalkyl group.
68. The compound of any one of claims 1-67, wherein R 16 Is an alkyl group.
69. The compound of any one of claims 1-67, wherein R 16 Is a heterocyclic group.
70. The compound of any one of claims 1-67, wherein R 16 Is aryl.
71. The compound of any one of claims 1-67, wherein R 16 Is heteroaryl.
72. The compound of any one of claims 1-67, wherein R 16 Is a bicyclic ring.
73. The compound of any one of claims 1-67, wherein R 16 Is a haloalkyl group.
74. The compound of any one of claims 1-67, wherein R 16 is-S (O) 2 -。
75. The compound of any one of claims 1-67, wherein R 16 is-C (O) -.
76. The compound of any one of claims 1-67, wherein R 16 is-C (O) O-.
77. The compound of any one of claims 1-67, wherein R 16 is-OC (O) -.
78. The compound of any one of claims 1-67, wherein R 16 is-O-.
79. The compound of any one of claims 1-67, wherein R 16 is-NR 10 -。
80. The compound of any one of claims 1-67, wherein R 16 Is a key.
81. The compound of any one of claims 1-79, wherein R 17 Is a key.
82. The compound of any one of claims 1-80, wherein R 17 Is an alkyl group.
83. The compound of any one of claims 1-80, whereinR 17 Is a heterocyclic group.
84. The compound of any one of claims 1-80, wherein R 17 Is aryl.
85. The compound of any one of claims 1-80, wherein R 17 Is heteroaryl.
86. The compound of any one of claims 1-80, wherein R 17 Is a bicyclic ring.
87. The compound of any one of claims 1-80, wherein R 17 Is a haloalkyl group.
88. The compound of any one of claims 1-87, wherein R 18 Is hydrogen.
89. The compound of any one of claims 1-87, wherein R 18 Is halogen.
90. The compound of any one of claims 1-87, wherein R 18 is-C (O) R 27 。
91. The compound of any one of claims 1-87, wherein R 18 is-C (O) OR 27 。
92. The compound of any one of claims 1-87, wherein R 18 is-C (O) NR 10 R 27 。
93. The compound of any one of claims 1-87, wherein R 18 is-NR 27 C(O)R 27 。
94. The compound of any one of claims 1-87, wherein R 18 is-NR 10 R 27 。
95. The compound of any one of claims 1-87, wherein R 18 is-OR 27 。
96. The compound of any one of claims 1-87, wherein R 18 Is aryl, optionally substituted with 1, 2, 3 or 4 groups independently selected from R, where the valency permits to form a stable compound 40 Is substituted by a substituent of (a).
97. The compound of any one of claims 1-87, wherein R 18 Is a heterocyclic ring, optionally substituted with 1, 2, 3 or 4 groups independently selected from R, where the valency permits to form a stable compound 40 Is substituted by a substituent of (a).
98. The compound of any one of claims 1-87, wherein R 18 Is heteroaryl, optionally substituted with 1, 2, 3 or 4 groups independently selected from R, where the valency permits to form a stable compound 40 Is substituted by a substituent of (a).
99. The compound of any one of claims 1-98, wherein R 10 And R is 11 Independently selected from hydrogen, alkyl and-C (O) R 12 。
100. The compound of any one of claims 1-99, wherein R 12 is-NR 13 R 14 OR 13 。
101. The compound of any one of claims 1-100, wherein R 13 And R is 14 Independently selected from hydrogen and alkyl.
102. A compound selected from:
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or a pharmaceutically acceptable salt thereof.
103. A pharmaceutical composition comprising a compound according to any one of claims 1-102, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
104. A method of treating a disorder mediated by a hydroxy cerebroside, IKZF2, and/or IKZF4 in a human comprising administering to a human in need thereof an effective dose of a compound according to any one of claims 1-102 or a pharmaceutically acceptable salt or composition thereof.
105. The method according to claim 104, wherein the disorder is mediated by IKZF2 or IKZF 4.
106. The method of claim 104 or 105, wherein the disorder is cancer or tumor.
107. The method of claim 104 or 105, wherein the disorder is an immune, autoimmune or inflammatory disorder.
108. The method of claim 104 or 105, wherein the disorder is a hematological malignancy.
109. The method of claim 104 or 105, wherein the disorder is small cell lung cancer, non-small cell lung cancer, melanoma, breast cancer, triple negative breast cancer, multiple myeloma, leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, or myelodysplastic syndrome.
110. A compound for use in the manufacture of a medicament for the treatment of a disorder mediated by hydroxy cerebroside, IKZF2 and/or IKZF4 in a human, wherein the compound is selected from any one of claims 1-102 or a pharmaceutically acceptable salt or composition thereof.
111. The compound of claim 110, wherein the disorder is mediated by Ikaros or Aiolos.
112. The compound of claim 110 or 111, wherein the disorder is cancer or tumor.
113. The compound of claim 110 or 111, wherein the disorder is an immune, autoimmune or inflammatory disorder.
114. The compound of claim 110 or 111, wherein the disorder is a hematological malignancy.
115. The compound of claim 110 or 111, wherein the disorder is small cell lung cancer, non-small cell lung cancer, melanoma, breast cancer, triple negative breast cancer, multiple myeloma, leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, or myelodysplastic syndrome.
116. Use of a compound selected from any one of claims 1-102 or a pharmaceutically acceptable salt or composition thereof in the treatment of a disorder mediated by hydroxy cerebroside, IKZF2 and/or IKZF4 in a human.
117. The use of claim 116, wherein the disorder is mediated by Ikaros or Aiolos.
118. The use of claim 116 or 117, wherein the disorder is cancer or a tumor.
119. The use of claim 116 or 117, wherein the disorder is an immune, autoimmune or inflammatory disorder.
120. The use of claim 116 or 117, wherein the disorder is a hematological malignancy.
121. The use of claim 116 or 117, wherein the disorder is small cell lung cancer, non-small cell lung cancer, melanoma, breast cancer, triple negative breast cancer, multiple myeloma, leukemia, chronic myelogenous leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, or myelodysplastic syndrome.
CN202180083722.6A 2020-10-14 2021-10-14 Tricyclic ligands for degradation of IKZF2 or IKZF4 Pending CN116783180A (en)

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